CN1747938A - Novel substituted 2,3-benzodiazepine derivatives - Google Patents
Novel substituted 2,3-benzodiazepine derivatives Download PDFInfo
- Publication number
- CN1747938A CN1747938A CNA200480003526XA CN200480003526A CN1747938A CN 1747938 A CN1747938 A CN 1747938A CN A200480003526X A CNA200480003526X A CN A200480003526XA CN 200480003526 A CN200480003526 A CN 200480003526A CN 1747938 A CN1747938 A CN 1747938A
- Authority
- CN
- China
- Prior art keywords
- methyl
- dihydro
- benzodiazepine
- dioxole
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Links
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- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
- C07D253/08—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 condensed with carbocyclic rings or ring systems
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- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
Abstract
The invention relates to new 2,3-benzodiazepine derivatives of formula (I), isomers and acid addition salts thereof and to pharmaceutical compositions containing the same, as well as to pharmaceutical compositions and methods of using the same suitable for treating conditions associated with muscle spasms, epilepsy, acute and chronic forms of neurodegenerative diseases as well as preventing, treating or alleviating the symptoms of acute and chronic inflammatory disorders.
Description
The mutual reference of related application
The application is the part continuation application of the application serial no 10/358,053 of submission on February 4th, 2003.
Background of invention
Invention field
The present invention relates to 2 of new heterocyclic substituted, 3-benzodiazepine derivative, its acid salt and the pharmaceutical composition that contains them.The invention still further relates to of the application of described compound as the ampa receptor antagonist.
Summary of related art.
Overactivity and several acute and chronic central nervous system (" the CNS ") disease-relateds with glutamate receptor joins.After deliberation multiple glutamate receptor antagonist as treatment mode (referring to for example Parsons etc., Drug News Perspect.
11: 523 (1998) and Br ǎ uner-Osborne etc., J.Med.Chem.
43: 2609 (2000)).
The glutamate receptor of AMPA (2-amino-3-(3-hydroxy-5-methyl base-4-isoxazolyl)-propionic acid) type plays an important role in multiple central nervous system disease.Verified, to the activatory of AMPA receptor suppress to have neuroprotective, anti-epileptic and myorelaxant effects (referring to for example, Cerebrovasc.Brain Metab.Rev.
6: 225 (1994); Neurology
44Suppl.8, S14 (1994); J.Pharmacol.Exp.Ther.
260: 742 (1992)).
Glutamate receptor not only finds in CNS, but also finds in peripheral tissues, the potential chance of treatment outside the hint CNS (referring to for example, skery etc., Trends inPharm.Sci.,
22: 74 (2001).Supposed that NMDA-type glutaminate antagonist can influence respiratory inflammation (Said, Trends in Pharm.Sci. valuably
20: 132 (1999); With Said etc., Trends in Pharm.Sci.,
22: 344 (2001)).
The AMPA receptor can be suppressed by multiple emulative and noncompetitive antagonist.The treatment of noncompetitive antagonist render a service may be better than emulative because their activity do not rely on high density the endogenous glutaminate (referring to for example, Vizi etc., CNS Drug Rev,
2: 91 (1996)).The most outstanding a kind of noncompetitive ampa receptor antagonist is 5-(4-aminophenyl)-8-methyl-9H-1; 3-dioxole also [4; 5-h] [2; 3] benzodiazepine (being also referred to as GYKI 52466); it has significant anti-epileptic, of flaccid muscles and neuroprotective activity (Tarnawa etc.; Eur.J.Pharmacol.
167: 193 (1989); Smith, etc., Eur.J.Pharmacol.,
187: 131 (1990); Quardouz etc., Neurosci.Lett.,
125: 5 (1991); Donevan etc., I.Neuron.,
10: 51 (1993)).
Put down in writing several noncompetitive AMPA antagonists in the literature, comprised 3,4-dihydro-5H-or 4; 5-dihydro-3H-2,3-benzodiazepine , it contains acyl group (referring to for example 3 of ring; hungarian patent number 206,719 B and 219,777 B; U.S. Patent number 5,536,832; European Patent Publication No 0,699 677 A1 and British Patent No. 2 311 779, and WO 96,/04 283; WO 97,/28 135, WO 99,/07 707, WO 99,/07 708 and WO 01,/04 122).WO 96,/06 606 is (with U.S. Patent number 5,795,886 correspondences) described and severally had 2 of aryl and heteroaryl substituting group (for example, pyridyl, thienyl, furyl, phenyl, imidazolyl, benzimidazolyl-etc.), 3-benzodiazepine derivative at C3.
Have been found that above-mentioned compound can be used for wherein detecting glutaminate system function over-drastic disease especially.Such CNS acute illness comprises for example apoplexy, cerebral ischaemia, brain and Spinal injury, perinatal hypoxia, hypoglycemia nerve injury etc.Other chronic disease that wherein can use the AMPA antagonist of selection comprises for example Alzheimer, huntington's chorea, amyotrophic lateral sclerosis, AIDS inductive dementia, glaucoma, diabetic retinopathy and Parkinson's disease.And, also (for example in the illness relevant with nerve injury, epilepsy, migraine, bladder incontinence, psychosis-anxiety disorder, schizophrenia etc., drug abuse, pathological pain, cerebral edema and tardive dyskinesia) in confirmed the enhanced activity of glutaminate system, hinting the tempting treatment potentiality of AMPA antagonist.
Recently, experimental data shows that the AMPA antagonist of selection has beneficial effect to the autoimmunity encephalomyelitis that causes in rat, and it is multiple sclerosis model (Smith etc., the Nature Medicine that generally acknowledges
6: 62 (2000)).In addition, AMPA in the spinal cord and nmda receptor have participated in the contraction of bladder and urethra, show that the AMPA antagonist can be used for the treatment of the urinary incontinence (Nishizawa etc., Adv.in Exp.Med.﹠amp; Biol.
4: 275 (1999)).
2 kind 2,3-benzodiazepine derivative GYKI 52466 (as above) and (R)-7-ethanoyl-5-(4-aminophenyl)-8,9-dihydro-8-methyl-7H-1; 3-dioxole also [4; 5-h] [2,3] benzodiazepine (GYKI 53773, are also referred to as Talampanel) is useful.Confirmed in clinical trial that the latter is activated (Bialer etc., Epilepsy Res. for the epileptic
43: 11 (2001)).
In addition, reported that GYKI 52466 can suppress the growth (Rzeski etc., Proc.Nat.Acad.Sci.98:6372 (2001)) of the tumor cell type (adenocarcinoma of colon, astrocytoma, mammary cancer, lung cancer and neuroblastoma) of selection.
Summary of the invention
The present invention relates to the new 2 of following formula (I), 3-benzodiazepine derivative, its isomer and its acid salt also relate to the pharmaceutical composition that contains them,
Wherein substituent implication is as follows:
R
3That representative replaces or unsubstituted 5-or 6-unit is aromatics, saturated or fractional saturation contain at least 2 heteroatomic heterocycles, wherein heteroatoms can be oxygen, sulphur or nitrogen-atoms, and when heterocycle contained 2 heteroatomss, one of them was not a nitrogen;
R
4, R
5, R
6And R
7Represent hydrogen atom, halogen atom, C independently of each other
1-C
3Alkyl, nitro or amino, wherein amino can be independently of each other by 1 or 2 following radicals replacement: C
1-C
3Alkyl, C
2-C
5Acyl group or C
2-C
5Carbalkoxy, or aminocarboxyl or C
2-C
5Alkyl amino-carbonyl; And
R
9Represent C
1-C
3The alkoxy or halogen atom,
R
10Represent hydrogen or halogen atom or
R
9And R
10Can form C together
1-C
3Alkylene dioxo base.
Representational compound includes but not limited to (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8, and 9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-propyl group-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-{5-[1-(1E)-propylene-1-yl]-1,3,4-thiadiazoles-2-yl }-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine and its acid salt also.
The invention also discloses formula (I) compound or the pharmaceutical composition of its steric isomer or its pharmacy acceptable salt and pharmaceutically acceptable solvent, thinner, carrier and weighting material, the wherein R that contain as activeconstituents
3-R
7, R
9And R
10Implication as defined herein.
Described compound is applicable to treatment and muscle spasm, epilepsy, the relevant illness of neurodegenerative disease acute and chronic form, and the symptom of preventing, treat or alleviate acute and chronic inflammatory disease.
With reference to the many publications relevant with the expansion therapeutic value of AMPA receptor antagonist, those skilled in the art can understand that compound of the present invention can be used for very many incoherent illnesss.
Therefore, treatment and acute or that chronic neurodegenerative disease is relevant or in the acute or chronic illness in eye relevant handicapped method of glutaminate are provided with the glutaminate dysfunction.Representational neurodegenerative disease comprises for example cerebral ischemia (apoplexy), brain and Spinal injury, Alzheimer, huntington's chorea, amyotrophic lateral sclerosis, AIDS inductive dementia, essential tremor, Parkinson's disease, multiple sclerosis and the urinary incontinence.Acute or the chronic illness in eye relevant with the glutaminate dysfunction comprises glaucoma or diabetic retinopathy.Also disclose the treatment epilepsy, alleviate muscle spasm, eased the pain or the method for inflammatory diseases, it comprises the compound of the present invention to the object administering therapeutic significant quantity of the such treatment of needs.Include the allergic inflammatory diseases of air flue in the inflammatory diseases, it can comprise allergic rhinitis, endogenous or extrinsic bronchial asthma, acute or chronic bronchitis, chronic obstructive pulmonary disease and pulmonary fibrosis.
Detailed Description Of The Invention
The patent of quoting in this article, disclosed application and scientific and technical literature have been set up those skilled in the art's knowledge, and they are whole here incorporated by reference, and its degree is with especially, individually to quote every piece identical as a reference.If any conflict takes place the certain teachings of any reference of here quoting and this specification sheets, should be as the criterion with the latter.Similarly, if any conflict takes place for the word of the special instruction of the definition of word that this area is understood or phrase and this specification sheets or the definition of phrase, should be as the criterion with the latter.
The invention discloses 2 of new replacement, 3-benzodiazepine derivative compound and their method of production.Also disclose and adopted 2 of new replacement, the pharmaceutical composition of 3-benzodiazepine derivative compound and their application in treatment numerous disease situation.
Except as otherwise noted, technology of using in this article and scientific terminology implication with those skilled in the art in the invention's common sense.In this article with reference to several different methods known to those skilled in the art and material.The canonical reference document of setting forth pharmacological General Principle comprises Goodman and Gilman ' s
The Pharmacological Basis of Therapeutics, 10
ThEd., McGraw Hill Companies Inc., New York (2001).Any suitable material known to the skilled and/or method may be used to realize the present invention.But, preferable material and method have been described.Except as otherwise noted, the material of mentioning among specification sheets below and the embodiment, reagent etc. can be buied from the commercial channel.
As employed in this manual, singulative " " and " being somebody's turn to do " also comprise the plural form of the term of their indications especially, unless its implication is clearly got rid of.For example, " antagonist " comprises the mixture of antagonist.
As employed in this manual, no matter be in transition phrase or claim, term " comprises/comprise " and should be understood to have open implication.That is to say that this term should be understood to " have at least " or " comprising at least " synonym with phrase.When in the context that is used in process, term " comprises/comprise " and is meant that this process comprises described step at least, but also can comprise other step.When in the context that is used in compound or composition, term " comprises/comprise " and is meant that this compound or composition comprise described feature or component at least, but also can comprise other feature or component.
Term " about " is used in reference to approximately in this article, about, roughly or on every side.When term " about " was used with digital scope, it was by extending to the border more than the described numerical value or with this scope of correction of getting off.Usually, term " about " is used for being adapted to more than the described value numerical value and following 20% deviation in this article.
As used herein, unless explanation is arranged especially in addition, " comprising " implication of the word of use " or " have " and/or ", rather than " or " " eliminating " implication.
As used herein, the statement of the numerical range of variable is intended to expression, uses the variable identical with the interior any value of this scope can realize the present invention.Thereby for discrete in nature variable, this variable can equal any round values of numerical range, comprises the end points of scope.Similarly, for successive variable in nature, this variable can equal any real-valued of numerical range, comprises the end points of scope.As an example, the variable that is described as having the value between the 0-2 for discrete in nature variable, can be 0,1 or 2, for successive variable in nature, can be 0.0,0.1,0.01,0.001 or any other real-valued.
Method intention of the present invention is used for can be from any Mammals of method benefit of the present invention.In such Mammals, first-selected human, although the present invention is not intended to be limited to this, and can be used for veterinary purpose.Thereby according to the present invention, " Mammals " or " Mammals that needs is arranged " comprises people and inhuman Mammals, and particularly domestic animal includes but not limited to cat, dog and horse.
Should be understood that to its object of using compound of the present invention and need not to suffer from specific faulted condition.In fact, before any generation of symptom, can prophylactically use compound of the present invention.The conversion of term " treatment ", " therapeutic ground " and these terms be used to comprise treatment, alleviate with the application that prevents.Therefore, as used herein, " treatment or mitigation symptoms " be meant, compare with the symptom of the individuality of not accepting such administration, alleviates, prevents and/or reverse the symptom of having used the individuality of compound of the present invention to it.
The benzodiazepine of following formula (II) and its isomer and acid salt thereof are the themes of number of patent application 10/358,053:
(II)
Wherein
R
1And R
2Represent hydrogen atom or C independently of one another
1-C
3Alkyl,
R
3Represent at least 2 the heteroatomic heterocycles that contain of aromatics, saturated or fractional saturation that replace or unsubstituted 5-or 6-unit, wherein heteroatoms can be oxygen, sulphur or nitrogen-atoms, and works as R
3When being 5-unit ring, one in the heteroatoms is not nitrogen;
R
4, R
5, R
6, R
7And R
8Represent hydrogen atom, halogen atom, C independently of each other
1-C
3Alkyl, nitro or amino, wherein amino can be independently of each other by 1 or 2 following radicals replacement: C
1-C
3Alkyl, C
2-C
5Acyl group or C
2-C
5Carbalkoxy, or aminocarboxyl or C
2-C
5Alkyl amino-carbonyl;
R
9Represent C
1-C
3The alkoxy or halogen atom,
R
10Represent hydrogen or halogen atom, or
R
9And R
10Can form C together
1-C
3Alkylene dioxo base.
The present invention relates to shown in following formula (I) formula (II) 2,3-benzodiazepine derivative:
R wherein
1And R
8Be hydrogen, R
2Be CH
3, R
4, R
5, R
6, R
7, R
9And R
10Implication as top definition, R
3Be to be selected from following group: isoxazole replacement or unsubstituted, isothiazole, thiazole, thiazoline, 4-thiazolinone, oxazole, oxazoline, 1,2,3-thiadiazoles, 1,3,4-thiadiazoles, 1,3,4-Thiadiazoline-2-ketone, 1,2,4-Thiadiazoline-3-ketone, 1,4,2-Evil thiazoline, 1,3,4-oxadiazole, 1,2,3-triazoles, 1,3,4-triazole, 1,2,3, the 4-thiatriazole, tetrazolium, 1,3-thiazine-4-ketone and 1,3,4-thiadiazine-4-ketone ring.
The heterocyclic substituent R of benzodiazepine ring
3Further can by-inter alia-one or more following substituting groups replace: C
1-C
6Alkyl, C
2-C
3Alkenyl, C
3-C
7Cycloalkyl, trifluoromethyl, C
1-C
3Alkoxyl group or phenyl, oxo, formyl radical, carboxyl or C
2-C
4Carbalkoxy, C
1-C
3Alkoxy methyl, hydroxymethyl (wherein said hydroxyl can by alkylation or acidylate), C
1-C
3Alkylthio methyl, cyano methyl or amino methyl (wherein said amino can by alkylation or acidylate).
The implication of alkyl comprises straight chain and alkyl side chain.The implication of alkenyl can be vinyl, 1-propenyl or 2-propenyl.The implication of halogen atom can be fluorine, chlorine, bromine or iodine atom.Amino can be unsubstituted or be replaced by 1 or 2 alkyl, and by the carbonic ether acidylate of aliphatic series or aromatic carboxylic acid or any kind.
In the situation of formula (I) compound, term " isomer " is meant the E and the Z isomer of two kinds of enantiomers and where applicable, and isomer should comprise diastereomer, tautomer and their mixture, for example racemic mixture.
The salt of formula (I) compound relates to the physiologically acceptable salt that forms with mineral acid or organic acid.Suitable mineral acid can be for example hydrochloric acid, Hydrogen bromide, phosphoric acid or sulfuric acid.Appropriate organic can be for example formic acid, acetate, toxilic acid, fumaric acid, succsinic acid, lactic acid, tartrate, citric acid or methylsulfonic acid.
Representational formula (I) compound includes but not limited to (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8, and 9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-propyl group-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-{5-[1-(1E)-propylene-1-yl]-1,3,4-thiadiazoles-2-yl }-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine and its acid salt also.
Preparation formula (I) and (II) compound in the following manner.From following formula (III) compound, make up corresponding to R
3Heterocycle:
R wherein
1-R
10Be such as top formula (I) and (II) in definition,
By known method or have the compound of following formula (IV) or from the following iso chromenilium salt with formula (IVa) of formula (IV) compound formation, wherein R
1, R
2, R
4, R
5, R
6, R
7, R
8, R
9And R
10Implication be as defined above:
Make formula (IV) or (IVa) compound with have the reaction of formula V or compound (VI):
H
2N-NH-R
3 H
2N-NH-R
11
(V) (VI)
R wherein
3Implication be as defined above, and R
11Implication be C
2-C
8Alkoxy carbonyl or aryl-alkoxy carbonyl,
Obtain formula (VII) or compound (VIII).
With formula (VII) or (VIII) hydroxyl of compound change into sulphonate, and a kind of intermediate in back is carried out closed loop by using highly basic, obtain formula (I), (II) or (IX) compound:
Perhaps, according to Mitsunobu (Synthesis, I:1 (1988)), with formula (VII) or (VIII) compound transform an accepted way of doing sth (I), (II) or (IX) compound.In formula (IX) compound, cracking R
11Group obtains formula (III) compound, and the latter is according to aforesaid processing method, transforms an accepted way of doing sth (I) or (II) compound.Then; if desired, in the formula that obtains according to any aforesaid method (I) or (II) in the compound, the reduction nitro; perhaps acidylate, alkylation amino; or after diazotization, amino by halogen atom or hydrogen atom exchange, or halogen atom is by transamination; in this way; convert it into another kind of formula (I) or (II) compound and/or separating isomerism body, if desired, salify.
Formula (III) and (IX) compound be chipal compounds, so formula (III) and (IX) be meant any one enantiomorph or its mixture.The different steric isomer of hydrazone derivative representative of the hemiketal type compound of formula (IV) and formula (VII) and (VIII), they are meant all single steric isomers and its mixture.R
11Group can be C
2-C
8Carbalkoxy, for example tert-butoxycarbonyl or benzyloxycarbonyl.
Formula (III) raw material is document known (U.S. Patent number 5,536,832 and British Patent No. 2,311,779, and WO 97,/28 135 and WO 01,/04 122).Hungarian patent numbers 219,777 and British Patent No. 2,311,779 have also been described formula (III) compound synthetic of optically-active.
By under the condition of the acid that has catalytic amount, make for example according to (J.Am.Chem.Soc. such as Anderson
117: 12358 (1995)) formula (IV) hemiketal of preparing from the phenyl-Virahol of the replacement of optically-active, with the alkoxy carbonyl-hydrazides that contains the carbalkoxy that easily to remove (for example tert.-butoxy-carbamate) reaction, can synthesize formula (III) compound of optically-active.For example exist under the situation of triethylamine then, formula (VIII) hydrazone that will obtain after will separating with methylsulfonyl chloride changes into the methylsulfonyl ester, for example, in alcoholic solution, use alkali, for example sodium-hydroxide treatment latter, production in ring-closure reaction (IX) benzodiazepine derivative.The substituting group of cracking N-3 atom (according to benzodiazepine ring numbering) then for example by hydrolysis or other method hydrogenolysis for example, is produced formula (III) compound of needs.Can use trifluoroacetic acid, hydrogen bromide or zinc bromide in methylene dichloride, to carry out the cracking of tert-butoxycarbonyl.
According to the method relevant known in the art with heterocyclic chemistry, from formula (III) compound begun to synthesize formula (I) or (II) heterocyclic moiety of compound (with R
3Substituting group is corresponding).
Can synthesize some formulas (I) or (II) compound, for example from having replaced 4 of thiocarbamyl, 5-dihydro-2,3-benzodiazepine derivative 3 of benzodiazepine ring.A kind of compound in back can be from 4 of formula (III), 5-dihydro-3H-2, and 3-benzodiazepine derivative obtains, and for example uses the potassium sulfocyanate in the acetic acid medium.Make obtain like this 4,5-dihydro-3-thiocarbamyl-3H-2,3-benzodiazepine and α-Lu Daitong or alpha-halogen aldolization, generate have a replacement or unsubstituted 2-thiazolyl group 2,3-benzodiazepine derivative.In similarly reacting,, can form the suitable compound that contains 3-thiazolinone ring if substitute alpha-halogen oxo-compound with the 2-halogenated carboxylic ester.
Above-mentioned contain 4 of thiocarbamyl group at 3 when making, 5-dihydro-2 is during 3-benzodiazepine and β-halogenated carboxylic ester (for example 3-ethyl bromide) reaction; can obtain so by 5; 6-dihydro-[1,3] thiazine-4-ketone is cyclosubstituted new 2,3-benzodiazepine derivative.
Can synthesize and contain 1,3,4-thiadiazoles group is as R
3Substituent formula (I) or (II) compound are for example by following mode.At first, from formula (III) 4,5-dihydro-3H-[2,3] benzodiazepine prepares trimethyl silyl derivative, its then with the thiophosgene reaction, generate thiocarboxylic acid chlorine.At last, handle the latter, generate the thiocarboxylic acid hydrazide derivatives with hydrazine.Make by 2 of carbon sulfonyl hydrazine (carbothiohydrazide) group replacement; 3-benzodiazepine derivative and acid anhydrides or acyl chloride reaction; by further acid treatment; the ring closure of carbon sulphur-N-acyl group hydrazides that the part that promotion obtains like this takes place; generate [1; 3,4] thiadiazolyl group-2,3-benzodiazepine .A kind of another kind of method of compound is after synthetic, makes the reaction of above-mentioned intermediate thiocarboxylic acid chlorine and sour hydrazides, then with the carbon sulfonyl hydrazine derivative that contains acyl group on the resulting N-endways of the acid treatment atom, generates cyclic products.
In similar reaction, for example,, can be contained [formula (I) of 1,3,4] oxadiazole rings or (II) benzodiazepine if with the sulphur binding reagents above-mentioned N-acyl group-thiocarboxylic acid hydrazide derivatives of mercuric acetate (II) processing for example.
4,5-dihydro-2,3-benzodiazepine -3-carbon sulfonyl hydrazine can be as heterocyclically substituted other the new formula (I) or (II) raw material of compound.For example, if with concentrated acid (for example hydrochloric acid) heating from N-methyl-carbamyl-carbon sulfonyl hydrazine that methyl isocyanate obtains, can obtain the new formula (I) that replaced by (5-oxo-4,5-dihydro-[1,3,4] thiadiazoles-2-yl) group or (II) compound so.If make the reaction of carbon sulfonyl hydrazine derivative and monobromo-acetic acid ester, can obtain containing 6-unit ring as R
3Substituent (5-oxo-5,6-dihydro-4H-[1,3,4] thiadiazine-2-yl)-[2,3] benzodiazepine derivative.If make carbon sulfonyl hydrazine derivative and alpha-halogen-ketone, the reaction of for example acetone dichloride, for example can form so (5-methyl-6H-[1,3,4] thiadiazine-2-yl)-[2,3] benzodiazepine .
Can obtain suitable sulfo-hydroxamic acid from [2,3] benzodiazepine -3-thiocarboxylic acid chlorine with azanol, it can change into heterogeneous ring compound by reacting with difunctional alkylating agent.In addition, can for example use methylene iodide from sulfo-hydroxamic acid derivs synthetic [1,4,2] Evil thiazole-3-bases-2,3-benzodiazepine .
Can prepare and contain 3-oxo-2,3-dihydro-[1,2,4] thiadiazoles-5-base group is as R
3Substituent formula (I) or (II) compound; for example; by making the reaction of unsubstituted formula (III) compound and phenyloxycarbonyl lsothiocyanates; with primary amine the phenyloxycarbonyl-thiocarbamyl-benzodiazepine that obtains is changed into N-alkyl-carbamyl-thiocarbamyl-benzodiazepine then; the latter and for example bromine reaction finish the ring closure between sulphur and the nitrogen-atoms.
By making the reaction of formula (III) compound and chloroethyl isocyanate, generate urea derivatives, under the situation that has sodium iodide and salt of wormwood, in dimethyl formamide, heat then, it is closed to finish ring, can synthesize and contain 4, and 5-dihydro-oxazoles-2-base group is as R
3Substituent formula (I) or (II) compound.
Contain 2-alkyl-thiazole-4-base group as R by making 3-bromo-ethanoyl-[2,3] benzodiazepine and suitable carboxylic acid thioamides reaction, can synthesizing
3Substituent formula (I) or (II) compound.
From 3-cyano group-2,3-benzodiazepine (use cyanogen bromide from formula (III) 2,3-benzodiazepine obtains) can synthesize (the 1H-tetrazolium-5-yl) that contain inter alia and (5-alkyl-[1,2,4] oxadiazole-3-yls) group as R
3Substituent 2,3-benzodiazepine .By under the situation that has ammonium chloride to exist, carbonitrile derivatives and sodiumazide are reacted in dimethyl formamide, can synthesize tetrazolyl compounds, if at first handle nitrile compound simultaneously with azanol, and make amidoxim and carboxylic acid anhydride or the acyl chloride reaction that obtains like this, it is suitable 1,2 then can to obtain, 4-oxadiazole based compound.
By at first reacting with methyl iodide, can contain 1,2 from 3-thiocarbamyl-[2,3] benzodiazepine derivative is synthetic, 4-triazolyl group is as R
3Substituent formula (I) or (II) compound are used the resulting S-methyl compound of hydrazine condensation then, handle the intermediate that forms like this with carboxylic acid anhydride or acyl chlorides.
Synthesis type (I) or (II) other exemplary method of compound be such, formula (IV) hemiketal is existed under the situation of acid catalyst and the heterocycle reagent react that is replaced by diazanyl group.Under the situation that exists hydrochloric acid as catalyzer, for example in Virahol or toluene, and may use the Dean-Stark device by heating, can carry out condensation reaction.In some cases, valuably at first with mineral acid for example perchloric acid hemiketal is transformed an accepted way of doing sth (IVa) isochromenilium salt, the latter and hydrazine reagent reaction are for example in Virahol.The formula that obtains like this (VII) hydrazone forms the mixture of steric isomer usually.They can further react, and for example exist under the situation of triethylamine, with the methylsulfonyl chloride reaction in methylene dichloride, handle the mesylate that obtains after the separation with the strong solution of alkali in the mixture of an alcohol or a pure methylene dichloride.By for example Mitsunobu reaction (Mitsunobu Synthesis
1: 1 (1981)), can realize encircling closed reaction.
If desired, the formula (I) that can will obtain by different methods with other reaction or (II) compound change into other formula (I) or (II) compound.For example, can be with heterocycle (R
3Substituting group) the reactive halogen atom in the side chain is exchanged for amino, for example by heating with excessive suitable amine, perhaps can contain the NH group of the heterogeneous ring compound of N by known method alkylation.Exist under the situation of potassium tert.-butoxide, can realize a kind of conversion in back with methyl iodide, for example under the situation of triazolyl compound.
Usually under room temperature or high temperature, exist catalyzer for example under the situation of Raney nickel, platinum or palladium, in polar solvent, carry out formula (I) or (II) reduction of the nitro in the compound.Except gaseous hydrogen, can also use other hydrogen source, for example hydrazine hydrate, ammonium formiate, potassium formiate or tetrahydrobenzene.Can reduce nitro, for example under the situation that has acid, use tin, perhaps, use tin chloride (II) by in alcohol, heating.By known method, for example alkylation, acidylate or Sandmeyer reaction, the amino group of can further deriving.
By following experiment, the formula of the present invention (I) or (II) the AMPA antagonistic activity of compound have been described.Compound by numeric reference is meant the compound described in the embodiment that numbers below.
The inhibition of ampa receptor
Use 2 experimental models come confirmation formula (I) or (II) compound the ampa receptor activatory is suppressed.In first model, studied the spreading depression that glutaminate agonist (that is, AMPA or kainate) causes, and in second model, directly detected AMPA/ kainate receptor activation inductive and striden the film ion(ic)current.
In the isolating chicken retina to the inhibition of AMPA inductive " spreading depression "
At external " spreading depression " model (Sheardown Brain Res.
607: 189 (1993)), studied the formula (I) or (II) the AMPA antagonist action of compound.The AMPA antagonist can prolong the latent period that " spreading depression " that AMPA (5 μ M) causes takes place.
Table 1
Inhibition to " spreading depression " in the chicken retina
Compound (embodiment numbering)/IC 50μM | |||||
GYKI 52466 (reference) | GYKI 53773 (reference) | 61 | 69 | 86 | 84 |
9.5 | 1.2 | 1-5 | 0.9 | 0.42 | 0.85 |
The data of table 1 show that compound of the present invention can suppress AMPA-inductive " spreading depression ", IC
50Value is 0.4-5 μ M.
Inhibition to AMPA inductive transmembrane current
According to (Neuropharmacology such as for example Bleakman
12: 1689 (1996)) described method, by detecting the full cell currents of 5 μ M AMPA inductive, on the cerebellum Purkinje cell of acute isolation, studied the activity of compound of the present invention.According to the IC that obtains
50Value, compound of the present invention can suppress AMPA-inductive ion(ic)current, than the IC that generally acknowledges in the world
50Value is respectively the reference compound GYKI 52466 (5-(4-aminophenyl)-9H-1 of 8.8 μ M and 1.57 μ M; the 3-dioxole is [4,5-h] [2,3]-benzodiazepine also; hungarian patent numbers 191 698) or GYKI 53773 ((R)-7-ethanoyl-5-(4-aminophenyl)-8; 9-dihydro-8-methyl-7H-1,3-dioxole be [4,5-h] [2 also; 3] benzodiazepine ; U.S. Patent number 5,536,832) big 1 to 2 order of magnitude (referring to table 2).
Table 2.
Pressing down of the ion(ic)current that 5 μ M AMPA are caused that records by full cell patch clamping method
System
Compound (embodiment numbering)/IC 50μM | |||||
GYKI 52466 (reference) | GYKI 53773 (reference) | 61 | 69 | 86 | 84 |
8.8 | 1.57 | 0.49 | 0.42 | 0.06 | 0.09 |
Anti-convulsant activity
Be used for treatment of epilepsy although have the multiple medicine of different activities spectrum, they show severe side effect.And about 30% epileptic can be to these medicine resistances.As a result, need so new antiepileptic drug, it plays a role by the mechanism different with the medicine of present use.To those can by reduce active compound that glutaminate-inductive central nervous system overactivity shows them exist very high expectation (TIPS,
15: 456 (1994)).
Use electroshock experiment (J.Pharmacol.Exp.Ther.
106: 319 (1952)), the anti-epileptic outbreak that has detected some compounds of the present invention is active, and the result is as shown in table 3.Use and for example be used to induce the pentetrazole (J.Pharmacol.Exp.Ther. of clonic spasm grand mal and lethality rate
108: 168 (1953)), Strychnine (J.Pharmacol.Exp.Ther.
129: 75 (1960)), bemegride, nicotine, eximine, 4-aminopyridine and sulfydryl-propionic acid, studied the spasmolysis activity of compound of the present invention.Generally inducing preceding 60 minutes of outbreak, with the compound of 3 dosage dosage forms for oral administration research, each dosage uses 10 male CD1 mouse.Unrestriced, indicative result is summarised in the table 3.
Table 3
Anti-convulsant activity in the research mouse
Method | Compound (embodiment numbering)/ED 50mg/kg po. | |||||||
GYKI 52466 | GYKI 53773 | 61 | 69 | 86 | 84 | 89 | 102 | |
MES | 37.4 | 8.6 | 13.1 | 14.7 | 6.1 | 12.5 | 10.5 | 13.9 |
MES 30’ | 21.9 | 4.9 | 11.5 | 8.7 | 4.3 | 10-15 | - | - |
Pentetrazole | 119.8 | 16.8 | 32.5 | 46.9 | 10.0 | 17.1 | 11.5 | 35.7 |
Strychnine | 86.7 | 17.4 | 35.4 | 27.7 | 10.6 | 18.2 | 15.7 | 26.7 |
Bemegride | 71.9 | 23.9 | 34.4 | 33.3 | 11.2 | 16.7 | 11.2 | 27.9 |
Eximine | 35.0 | 14.6 | 31.0 | 18.1 | 4.6 | 17.0 | 17.1 | 25.8 |
Nicotine | 71.8 | 22.7 | 59.3 | 16.8 | 16.5 | 77.2 | 45.9 | 31.7 |
4-AP | 43.0 | 8.4 | 17.6 | 16.6 | 10.1 | 16.6 | 14.3 | 20.4 |
3-MPA | 47.0 | 17.1 | 11.0 | 34.2 | 4.0 | 6.8 | >50 | >50 |
Abbreviation: MES=maximal electroshock outbreak; The 4-AP=4-aminopyridine; 3-MPA=3-sulfydryl-propionic acid
Above-mentioned data show, formula of the present invention (I) or (II) compound in whole 8 research experiments, show significant anti-convulsant activity.Compare with GYKI 53773 with the GYKI52466 that is used as reference compound in the literature, they show wider spectrum and more significant anticonvulsion effectiveness.To the provide protection that different convulsions inductors shows, their potential application in the different types of epilepsy of treatment have advantageously been indicated.
Muscle relaxant activities
The maincenter muscle relaxant is used for such clinical setting, wherein because brain damage or because chronic neurodegenerative disease has increased the rest tension of skeletal muscle, causes muscle rigidity or trembles.Muscle spasm often is a pain, and can hinder normal motion.
At the described sieve experiment (J.Pharmacol.Exp.Ther. that inclines of Randall
129: 163 (1960)) and at rotarod test (Dunham etc., J.Am.Pharm.Assoc.
46: 208 (1957)), detected the formula of the present invention (I) or (II) muscle relaxant activities of compound.Use 10 CD1-mouse/dosage, with 3 dosage intraperitoneal administered compounds.With the muscle relaxant activities of compound of the present invention and comparing of reference compound GYKI 52466 and GYKI 53773.Representational, unrestriced result is summarised in the table 4.From these data as can be seen, the muscle relaxant activities of compound of the present invention has surpassed the activity of GYKI 53773 significantly, and the latter is in the II phase clinical study now.
Table 4
Muscle relaxant activities in the mouse
Compound (embodiment numbering) | Sieve ED inclines 50Intraperitoneal (mg/kg) | Rotarod ED 50Intraperitoneal (mg/kg) |
GYKI 52466 (reference) | 47.1 | 25.1 |
GYKI 53773 (reference) | 13.4 | 2.3 |
61 | 10.7 | 5.4 |
69 | 12.2 | 1.2 |
86 | 3.9 | 0.8 |
84 | 12.8 | 1.4 |
89 | 4.3 | 1.7 |
102 | 14.8 | 2.9 |
The formula that detects in the superincumbent experiment (I) or (II) muscle relaxant activities of compound shown potential therepic use in the disease that the muscle tone that treatment wherein increases can have problems.Consider their skeletal muscle relaxation and the antidetonation activity (following discussion) of quivering, described compound can be used for the treatment of essential tremor, multiple sclerosis (spasm+tremble) and Parkinson's disease (tetanic+as to tremble).
To ischemic inhibition
(MCAO) test (Bartus Stroke by " middle cerebral artery occlusion "
11: 2265 (1994) and Sydserff etc., Brit.J.Pharmacol.
114: 1631 (1995)), detected the formula of the present invention (I) or (II) the local ischemia resisting activity of compound.After the halothane anesthesia, do not cut skull, after this blood of the left middle cerebral artery of the embolus temporary interruption anesthetized rat of introducing with intra-arterial take out embolus for (60 minutes), rebulids perfusion, thus " apoplexy-sample " state that in experimental animal model, triggers the people.After the histology process after 24 hours (TTC dyeing), detect infarct size, and compare with result that control group with media processes obtains by computer assisted scanning sequence.Unrestriced, representational result is summarised in the table 5.
Table 5.
Ischemic inhibition in the rat
Compound (embodiment numbering) | Dosage mg/kg intravenously (6x, per 30 minutes) | Compare infarct size with control group and reduce % | ||
30 minutes | 120 minutes | 180 minutes | ||
The time of blocking the back first treated | ||||
GYKI 52466 HCl (reference) | 2 | 39* | ||
5 | 34* | 47** | ||
GYKI 53773 (reference) | 2 | 47* | 49** | 26 |
61 | 1 | 63** | 16 | |
2 | 46* | |||
69 | 2 | 28 | ||
86 | 1 | 35* |
* p<0.05; * p<0.01; Carry out the Dunnett check according to ANOVA and calculate (Dunnett J.Amer.Statist.Ass.
50: 1096 (1955))
The compound of research has stronger neuroprotective activity in this experimental model (thinking the model of people's apoplexy).Some compounds, those described in the embodiment 61 and 86 for example, even when obstruction administration in back 3 hours, also can show significant activity, indicated the potential useful clinical application.
Inhibition to the autoimmunization inflammation
Multiple sclerosis is the chronic autoimmunization inflammation of central nervous system, guarantees that wherein the aixs cylinder myelin layer of the conduction of impulse of safety is damaged.The oligodendrocyte that forms the myelin layer is mainly expressed AMPA/ kainate acceptor.Thereby, further strengthen neurodegenerative process by activated by a large amount of glutaminates (excitatoty neurotransmitter) that discharge of its active immunocyte of AMPA/ kainate expression of receptor, destroyed myelin oligodendrocyte and neuronic aixs cylinder (Steinman Nature Medicine thus
6: 15 (2000) and Werner etc., J.Neurol.Transmiss.Suppl.,
60: 375 (2000)).As the result of these processes, slight neurological symptoms result (for example vision, sensation, balance, motion and urogenital problem) originally takes place, increase the weight of gradually.The treatment of multiple sclerosis remains open question, although carried out furtheing investigate (Bjartmar etc., Drugs of Today in this area
38: 17 (2002)).
Muscle spasm state and intetion tremor belong to the most serious neurological symptoms result (Baker etc., the Nature of multiple sclerosis
404: 84 (2000)).It is very important alleviating or cure these symptoms by suitable therapy.
Use cavy myelin basic protein (MBP) and complete Freund's adjuvant to carry out immunity, the autoimmunity encephalomyelitis model of rat (Smith etc., Nature Medicine,
6: further studied 62 (2000)) and had 2 of AMPA antagonistic activity, the activity of 3-benzodiazepine derivative.After the immunity the 10th day, every day, 2 intraperitoneal administered compounds carried out 8 days, and observed at the symptom duration of existence.In every group, use 5-15 animal.Their weight is 160-180g (Lewis rat, female) and 180-220g (Lewis rat, male).Determine the activity of compound according to the symptom fractional value, and compare (referring to table 6) with control group.Use 5-10 animal/group, on brain stem, spinal cord and sciatic nerve, carry out histopathological study (Gijbels etc., J.Clin.Invest.
94: 2177 (1994)).Nonrestrictive, representational result is as shown in table 7.
Table 6.
Have 2 of AMPA antagonistic activity, 3-benzodiazepine is to self of Lewis rat
The effect of the clinical symptom of immunity encephalomyelitis
Compound (embodiment numbering) | Dosage (mg/kg intraperitoneal) | Neurological symptoms result (variation compared with the control, %) | |||
Female rats 0-8 days | 0-14 days | Male rat 0-8 days | 0-14 days | ||
GYKI 53773 (reference) | 30 15 | -38* -60* | -27 -63** | -43* -8 | -29 +7 |
GYKI 52466 (reference) | 30 | -45 | -4 | -1 | -1 |
86 | 15 7.5 3.75 1.875 | -97** -62** -3 -40* | -85** -66** -18 -39* | -93* -65** -70** +5 | -67 -70** -77** -8 |
61 | 7.5 3.75 1.875 | -56* -44 -18 | -53* -48 -7 | -60* -44* +13 | -63** -46* +5 |
69 | 7.5 3.75 | -29 +43 | -24 +58* | -51* +35 | -50* -40* |
* p<0.05; * p<0.01 (Mann-Whitney check)
Table 7.
Has 2 of AMPA antagonist feature, 3-benzodiazepine derivative back 24 days to immunity
The influence of the histology of autoimmunity encephalomyelitis and clinical symptom in the Lewis rat
Compound (embodiment numbering) | Dosage (mg/kg intraperitoneal) | The histology symptom (changes, %) | Neurological symptoms result (changes, %) | ||
Rat is male | Female | Rat is male | Female | ||
GYKI 53773 (reference) | 30 | +34 | -16 | -26 | -41 |
86 | 15 7.5 3.75 1.875 | -66 +1 +4 -25 | -53 -22 -20 -15 | -67 -66 -72 +54 | -85 -62 -21 -42 |
61 | 7.5 | -20 | -5 | -54 | -53 |
According to our histopathology and pharmaceutical research, confirmed that for example embodiment 86 and 61 described compounds more have activity than reference compound GYKI 53773.
Use the agent of trembling that causes of 3 kinds of different mechanisms of action, for example oxotremorine (Rathbun etc., Psychopharmacology,
4: 114 (1963)), GYKI 20039 (3-(2, the 6-dichlorophenyl)-2-imino--thiazolidine; (Andr á si etc., Acta Physiol.Acad.Sci.Hung.
37: 183 (1970)) and Ha Maling, studied 2 of in the mouse model AMPA of having antagonist feature of the present invention, the antidetonation effect of quivering of 3-benzodiazepine derivative.Size of animal: 5/ group.Animal weight: 20-25g (CD1 mouse, male).By with their fractional value and comparing of control group, detected the activity of the compound of research.According to the Litchfield-Wilcoxon method, calculated ED
50Value, listed as table 8.
Table 8.
Have 2 of AMPA antagonist feature, 3-benzodiazepine derivative is to different chemistry
The effect of trembling of agent inductive CD1 mouse
Compound (embodiment numbering) | Dosage range (mg/kg p.o.) | ED 50(mg/kg po.) | ||
Oxotremorine 1mg/kg intraperitoneal | GYKI 20039 10mg/kg intraperitoneal | Ha Maling 40mg/kg intraperitoneal | ||
GYKI 52466 (reference) | 6.25-75.0 | 20.5(14.9-28.3) | 37.1(25.2-54.7) | 38.5(25.7-57.9) |
GYKI 53773 (reference) | 3.125-20.0 | 5.6(3.6-8.5) | 10.6(7.2-15.5) | 9.0(-7.4-10.9) |
86 | 3.125-9.0 | 4.3(3.5-5.4) | 6.8(5.5-8.5) | 6.0(4.9-7.4) |
According to our research, embodiment 86 described compounds more have activity than reference compound GYKI53773 and GYKI 52466 respectively.
Have 2 of AMPA antagonist feature, 3-benzodiazepine derivative can be by blocking the deleterious effect that corresponding acceptor compensates glutaminate, and this is important in treatment.Character such as the neuroprotective of their combination, of flaccid muscles, the inhibition of trembling can influence the progress of pathologic sacred disease valuably respectively and alleviate the pathologic neurological symptoms result.
Compound of the present invention is to the effect of acute and chronic air flue inflammatory diseases
Bronchial hyperreactivity (BHR) and air flue eosinophilia (AEP) are the features of bronchial asthma.The feature of BHR is the overreaction to multiple stimulation, and it can induce the resistance to the air-flow in the air flue to increase.AEP is the result of the eosinocyte infiltration, mastocyte and the T cell activation that prolong in the air flue.In the rat (for example, brown Norway [BN] strain) of initiatively (for example, Protalbinic acid) immunity, repeat sensitization and carry out the antigenicity attack subsequently and can cause ensinophilosis and bronchial hyperreactivity different spasmogens (for example, vagusstoff).This is the most frequently used model that is used to study the potential antiasthmatic effect of new chemical entities.
With allergen (Protalbinic acid) active immunity the BN rat.At first day, subcutaneous administration was suspended in Al (OH)
3In Protalbinic acid (2.5 μ g Protalbinic acids+20mg Al (OH)
3, in 0.5ml salt solution) and the sensitization rat.At the 14th and 21 day, carry out booster shots (same dose and identical approach).Simultaneously, each time, peritoneal injection 0.25ml Bordetella pertussis (Bordatella pertussis) vaccine.At the 28th day, attack animal (the 1%OVA solution of vaporization, 1 hour) by sucking antigen. in attack preceding 2 hours, the dosage forms for oral administration experimental compound.
Attacked back 48 hours, and put to death them, obtain bronchoalveolar lavage fluid (BALF) and excise tracheae from animal with excessive urethane (intraperitoneal is used 4-5ml 15% urethane).Use eosinophilic selective dye, and the cell in the counting Buerker chamber, the eosinophilic cell counting (cell/ml BALF) of manual mensuration.Use is suspended in the tracheal ring in the organ bath, detects BHR.After the balance 30 minutes, detect cumulative concentration response curve to vagusstoff.10
-3The M vagusstoff has obtained the maximum reaction of contrast (not attacking, untreated) tracheal ring.The height of this reaction is defined as 100%.All other contractions are expressed as per-cent with respect to control reaction.
The result
Table 9.
GYKI 52466 (reference), GYKI 53773 (reference) and embodiment 86 described chemical combination
Thing is to the Protalbinic acid sensitization and air flue carry out the BN-rat that antigen attacks by suction
Bronchial hyperreactivity and the effect of eosinophilia (mean+/-standard error, logical
Cross Student ' s t-check and determine p).
Compound (embodiment numbering) | ||||
Experiment | Parameter | Contrast | Attack | GYKI 52466 (reference) 3.0mg/kg po |
1 | ED 50* | 5.63±0.46 | 6.74±1.45 | 5.60±1.53 |
p | 0.002 | 0.028 | ||
MAX** | 100±0 | 276±217 | 135±105 | |
p | 0.001 | 0.037 | ||
Eosinocyte * * * | 0.17±0.01 | 1.24±0.23 | 0.91±0.13 | |
p | 0.010 | NS | ||
Experiment | Parameter | Contrast | Attack | GYKI 53773 (reference) 3.0mg/kg po |
2 | ED 50* | 5.22±0.59 | 5.89±0.66 | 4.64±0.91 |
p | 0.003 | 0.001 | ||
MAX** | 100±0 | 163±65 | 85±43 | |
p | <0.001 | 0.007 | ||
Eosinocyte * * * | 0.38±0.11 | 1.24±0.13 | 1.29±0.11 | |
p | 0.004 | NS | ||
Experiment | Parameter | Contrast | Attack | 86 3.0mg/kg po |
3 | ED 50* | 5.78±0.17 | 6.99±0.32 | 4.95±0.59 |
p | 0.001 | 0.008 | ||
MAX** | 100±0 | 255±50 | 81±14 | |
p | 0.001 | 0.003 | ||
Eosinocyte * * * | 0.23±0.08 | 1.43±0.27 | 1.32±0.32 | |
p | 0.005 | NS |
* can cause 50% vagusstoff (Ach) concentration (log M) of shrinking compared with the control
* is in the relative contraction compared with the control of maximum Ach concentration
* * BALF eosinocyte number (x10
6/ ml)
Not remarkable (p>0.05)
Representational result shown in the table 9 shows, according to representational compounds for reducing of the present invention the bronchial hyperreactivity that causes of allergen.Eosinophilia is not subjected to the remarkably influenced of application dose.
The result of above-mentioned different pharmaceutical research shows, formula of the present invention (I) or (II) compound can influence multiple disease and the obstacle that wherein relates to glutaminate (AMPA/ kainate) acceptor valuably.As a result, compound of the present invention is applicable to the neurologic and psychiatric disease of treatment by extreme enhanced ampa receptor triggered.Therefore, they have the therepic use as anticonvulsive drug, muscle relaxant and neuroprotective.They also show in the treatment epilepsy and wherein relate to the various disease of spasm of skeletal muscle and the treatment neurodegenerative disease therapeutic value in the cerebral ischemia (apoplexy) for example.
The exemplary neurological disorder that can influence valuably or prevent comprises Parkinson's disease, Alzheimer, huntington's chorea, amyotrophic lateral sclerosis, olivopontocerebellar atrophy, AIDS dementia, senile dementia.In the treatment of the neurodegenerative process that causes by cerebrovascular disease (apoplexy, brain and Spinal injury) or hypoxemia, anoxic or hypoglycemia, can realize similar beneficial effect.Compound of the present invention can be used for the treatment of different psychiatric disorders valuably, for example anxiety, schizophrenia, somnopathy, and the withdrawal symptom that alleviates alcohol and drug abuse.And the tolerance that they can be used to be suppressed under the situation of tranquilizer or anodyne produces.
Can expect that they can be used for the epileptic valuably, cure or alleviate the muscle spasm of maincenter origin and alleviate pathology pain and the treatment urinary incontinence.
The activatory method of one or more excitatory amino acid receptors in the blocking-up Mammals is provided in one aspect of the invention.This method comprises, gives the administration that needs this treatment pharmaceutically formula of significant quantity (I) or (II) compound.
In another aspect of the present invention, provide the method for the treatment of mammiferous epilepsy.This method comprises, gives the formula (I) of the administration anti-epileptic amount that needs this treatment or (II) compound.
In another aspect of the present invention, provide the method for the spasm of treatment mammalian skeleton musculation.This method comprises, gives the formula (I) of the administration amount of flaccid muscles that needs this treatment or (II) compound.
In another aspect of the present invention, provide the method for the treatment of mammiferous acute and chronic neurodegenerative disease.This method comprises, gives the administration that needs this treatment pharmaceutically formula of significant quantity (I) or (II) compound.
In another aspect of the present invention, provide the method for the treatment of mammiferous inflammatory diseases.This method comprises, gives the administration that needs this treatment pharmaceutically formula of significant quantity (I) or (II) compound.
In others of the present invention, formula (I) or (II) compound can be advantageously used in the treatment multiple sclerosis.Formula (I) or (II) operable other treatment field of compound be the disease that the function of periphery glutamate receptor excessively causes.Such disease comprises the acute and chronic inflammatory disease, particularly allergic inflammation of air flue, for example relevant with asthma pathology.The result who obtains in the rat of Protalbinic acid sensitization has supported back a kind of potential treatment to use.
In one aspect of the invention, the pharmaceutical composition that provides comprises formula (I) or (II) compound or its steric isomer or its pharmacy acceptable salt and pharmaceutically acceptable carrier, vehicle or thinner.
Use well-known arbitrarily pharmaceutically acceptable carrier, comprise thinner and vehicle (referring to
Remington ' s Pharma ceutical Sciences, 18
ThEd., Gennaro, Mack Publishing Co., Easton, PA 1990 Hes
Remington:The Science And Practice of Pharmacy, Lippincott, Williams ﹠amp; Wilkins, 1995), with formula (I) or (II) compound be formulated in the pharmaceutically acceptable medium.Although the kind of the pharmaceutically acceptable carrier/medium that adopts when producing composition of the present invention becomes with the pattern to the administration said composition, pharmaceutically acceptable carrier generally is an inert and nontoxic on the physiology.The preparation of pharmaceutical composition can contain more than one type formula (I) or (II) compound and any other pharmacologically active principles that can be used for the treatment of particular disorder, disease or the symptom that will treat.
Can be (for example by standard way, per os, suction, rectum, intranasal, partial, comprise suck with the hypogloeeis, or parenteral, comprise subcutaneous, intramuscular, intravenous, intracutaneous, transdermal with endotracheal) use composition of the present invention.In addition, can add polymkeric substance, to continue to discharge specific compound according to the standard method of this area.
For dosage forms for oral administration, composition of the present invention can be made discrete unit, for example capsule, capsule sheet, soft capsule, cachet, pill or tablet, and each contains the activeconstituents of predetermined amount, and it is powder or particulate state; Be solution in waterborne liquid or the non-aqueous liquid or suspension; Or be oil-in-water milky liquid liquid or water-in-oil emulsion and for injecting agent etc.Perhaps, by liquor, suspension or elixir, powder, lozenge, micronized particle and osmotic delivery system, can use and comprise formula (I) or (II) compound compositions.
The preparation that is suitable for inhalation comprises, the preparation that can be distributed by suction apparatus known to those skilled in the art.Such preparation can comprise carrier, for example powder and aerosol.Also comprise the liquid that is applicable to application in spraying and the segmental bronchus and the composition of powdered, or the aerosol combination of using by aerosol unit's distribution and computation dosage (" MDI ").
Activeconstituents can be formulated in the pharmaceutically acceptable suction medium of water-based, for example in the medium of isotonic saline solution or bacteriostatic water and other kind well known in the art.By means of the spray dispenser of pump or extruding-realization atomizing, or suck any other ordinary method of patient's lung by the liquid composition that is used for causing or realize required dosage, use solution.
Exemplary powder composition comprises, the preparation of pharmaceutically acceptable powdered is wherein used acceptable lactose in activeconstituents and the segmental bronchus or other inert powder thoroughly mixes.Can pass through the dispenser therefor powder composition, include but not limited to aerosol dispenser, or be encapsulated in the frangible capsule that the patient can insert the latter in the device, this device pierces through capsule and the mode of powder with current stabilization is blown out.
The aerosol formulation that uses in subject methods typically comprises propelling agent, tensio-active agent and solubility promoter, and in the conventional aerosol container of can packing into, the latter closes by suitable metering valve.
The preparation (wherein carrier is a solid) that is suitable for nasal administration comprises particle size range and is for example coarse meal of 20-500 micron, and it is used in the snuffing mode, promptly by sucking fast near the powder container of nasal meatus lifting nose.That for example be used for comprising water-based or butyrous formula (I) or (II) compound solution by nose spraying, aerosol or the appropriate formulation (wherein carrier is a liquid) used as nasal drops.
The preparation that is suitable for parenteral administration comprises water-based and nonaqueous aseptic injectable solution, and it can contain oxidation inhibitor, stablizer, buffer reagent, fungistat and make preparation and the isoosmotic solute of the blood of target recipient; With water-based and nonaqueous sterile suspensions, it can comprise suspension agent and thickening material.
The dosage of activeconstituents depends on the kind of route of administration, disease and seriousness and patient's body weight and age.The per daily dose of adult patients can be 0.1-500mg, preferred 1-100mg, with single dose or be divided into several dosage.
In another aspect of the present invention, a kind of method is provided, be used for the treatment of: (a) the acute or chronic neurodegenerative disease relevant with the glutaminate dysfunction; (b) be used for the treatment of the method for epilepsy; (c) be used to alleviate the method for mammiferous muscle spasm; (d) be used to prevent, treat or alleviate the method for symptom of the acute or chronic inflammatory disease of air flue; (e) be used for the method for the pathological pain of releasing mammal.These methods comprise, give the formula (I) of the administration treatment significant quantity that needs this treatment or (II) compound.
Term " treatment significant quantity " is used for expression, with the treatment of the dosage of the treatment result that can realize effectively looking for.And, the technician can understand, by fine tuning and/or by using, or, can reduce or improve the treatment significant quantity of compound of the present invention by using compound of the present invention with another kind of pharmacologically active chemical compounds more than a kind of compound of the present invention.Therefore, the invention provides the method that makes administration adapt to the concrete particularly urgent incident of specific Mammals.As described in the following examples, by from relatively low amount, also progressively increase, estimate beneficial effect simultaneously for example empirically, can easily determine the treatment significant quantity,
Those skilled in the art can understand, and is different with the patient according to the application times of compound of the present invention, based on this patient at the concrete medical condition of specified time arbitrarily.
The following examples describe in detail according to compound of the present invention and their method of preparation.
The following examples are used for further explaining some preferred embodiment of the present invention, and do not limiting in nature.Only by conventional experiment, those skilled in the art can recognize the numerous equivalents that maybe can determine predetermined substance as herein described and method.
Embodiment
The following raw material that synthesizes embodiment:
(±)-8-methyl-5-(4-nitrophenyl)-7-thiocarbamyl-8, the 9-dihydro
-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine (I) also
At 100-110 ℃, stir 0.90g (9.26mmol) potassium sulfocyanate, 2.00g (6.15mmo l) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture 6 hours of [2,3] benzodiazepine and 40ml acetate.After the cooling, leach sedimentary crystallization, wash with water and drying, generate 1.80g (76%) title compound.Fusing point: 242-243 ℃.
According to top method, synthesized thiocarbamyl Compound I I-X from corresponding dihydro-[2,3] benzodiazepine .
(R)-and 8-methyl-5-(4-nitrophenyl)-7-thiocarbamyl-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (II)Fusing point: 213-215 ℃.Productive rate: 73%, [α]
D:-251 ° of (c=0.5; CHCl
3).
(S)-and 8-methyl-5-(4-nitrophenyl)-7-thiocarbamyl-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (III)Fusing point: 213-214 ℃.Productive rate: 76%, [α]
D:+252 ° of (c=1; CHCl
3).
(±)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-thiocarbamyl-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (IV)
Fusing point: 230-236 ℃.Productive rate: 86%.
(±)-8-chloro-4-methyl-(4-nitrophenyl)-3-thiocarbamyl-4, the 5-dihydro
-3H-[2,3] benzodiazepine (V)
Fusing point: 261-265 ℃.Productive rate: 72%.
(±)-7,8-two chloro-4-methyl isophthalic acids-(4-nitrophenyl)-3-thiocarbamyl-4,5-two
Hydrogen-3H-[2,3] benzodiazepine (VI)
Fusing point: unbodied. productive rate: 59%.
(±)-8-methyl-5-phenyl-7-thiocarbamyl-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (VII)
Fusing point: 225-235 ℃.Productive rate: 86%.
5-(4-nitrophenyl)-7-thiocarbamyl-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (VIII)
Fusing point: 235-238 ℃.Productive rate: 62%.
(±)-8-methyl-5-(4-methyl-3-nitro phenyl)-7-thiocarbamyl-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (IX)Fusing point: 201-202 ℃.Productive rate: 84%.
(±)-7-bromo-4-methyl-8-methoxyl group-1-(4-nitrophenyl)-3-thiocarbamyl
-3,4-dihydro-3H-[2,3] benzodiazepine (X)
Fusing point: 250-253 ℃.Productive rate: 94%.
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl (carbothioyl) muriate (XI)
By heating, with 3.25g (10.0mmol) (±)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine is dissolved in the 90ml dry toluene, add 2.17ml (15.5mmol) triethylamine after, with 1.90ml (15.0mmol) trimethylsilyl chloride in about 28-30 ℃ reaction., after 16 hours this reaction mixture was dropwise added in the solution of 1.38g (12.0mmol) thiophosgene in the 30ml dry toluene through about 2 hours in stirring at room.In this mixture of stirring at room 5 hours, use the 30ml dilution with toluene then.Decompose by adding 30ml water then.After the separation, use 30ml water washing toluene 2 times mutually, wash with 10% sodium chloride aqueous solution then.After the drying, evaporating solvent is handled resistates with Di Iso Propyl Ether, generates the thick product of 3.27g (81%).
Recrystallization crude product from chloroform, sherwood oil.
Productive rate: 3.05g.Fusing point: about 185 ℃ of its recrystallize, then 210 ℃ of fusions.
By similar method, synthesized the compounds X II-XVII of carbon sulfenyl muriate type from dihydro-[2,3] benzodiazepine derivative of racemic or optically-active:
(R)-and 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate (XII)
Fusing point: 187-188 ℃.Productive rate: 80%, [α]
D:-610 ° of (c=0.5; CHCl
3).
(±)-8-methyl-5-(3-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate (XIII)
Fusing point: 198-199 ℃.Productive rate: 79%.
(±)-8-methyl-5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate (XIV)
Fusing point: 210-215 ℃.Productive rate: 79%.
(±)-8-methyl-5-(4-methyl-3-nitro phenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate (XV)
Fusing point: 201-202 ℃.Productive rate: 84%.
(±)-8-chloro-4-methyl isophthalic acid-(4-nitrophenyl)-4,5-dihydro-3H-[2,3] benzodiazepine
Assorted -3-carbon sulfenyl muriate (XVI)
Fusing point: 210-214 ℃ (DMF). productive rate: 70%.
(±)-7-bromo-4-methyl-8-methoxyl group-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3]
Benzodiazepine -3-carbon sulfenyl muriate (XVII)
Fusing point: 199-204 ℃.Productive rate: 82%.
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfonyl hydrazine (carbothiohydrazide) (XVIII)
At 5-10 ℃, 1.0g (2.47mmol) carbon sulfenyl muriate XI was added in the solution of 0.37g (7.42mmol) hydrazine hydrate in the 15ml tetrahydrofuran (THF) that stirs through about 0.5 hour, then after stirring 1 hour, mixture is poured in the water, leach sedimentary product, generate 0.89g (90%) crude product.After the drying, be used for further reactions steps.The fusing point of the product in ethanol behind the recrystallization is 196 ℃.
Synthesized carbon sulfonyl hydrazine derivative XIX-XXII by similar method:
(R)-and 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfonyl hydrazine (XIX)
Fusing point: 140-142 ℃.Productive rate: 99%, [α]
D:-201 ° of (c=0.5; CHCl
3).
(±)-8-chloro-4-methyl isophthalic acid-(4-nitrophenyl)-4,5-dihydro-3H-[2,3] benzodiazepine
Assorted -3-carbon sulfonyl hydrazine (XX)
Fusing point: 210-211 ℃.Productive rate: 61%.
(±)-7-bromo-4-methyl-8-methoxyl group-1-(4-nitrophenyl)-4.5-dihydro-3H-[2.3]
Benzodiazepine -3-carbon sulfonyl hydrazine (XXI)
Fusing point: 196-201 ℃.Productive rate: 98%.
(±)-8-methyl-5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfonyl hydrazine (XXII)
Fusing point: 188-190 ℃.Productive rate: 98%.
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-nitrile (XXIII)
With 3.25g (10mmol) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine , 20ml dimethyl formamide, 2.76g (20mmol) Repone K and 1.80g (17mmol) cyanogen bromide is stirring at room 20 hours.After pouring in the water, leach sedimentary crystallization, wash with water, generate 3.34g (95%) title compound, fusing point: 172-176 ℃.
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbamidoxime (XXIV)
The mixture of 2.80g (8.0mmol) compounds X XIII, 30ml 2-methyl cellosolve, 0.84g (10mmol) sodium acetate and 0.60g (8.8mmol) oxammonium hydrochloride was stirred 0.5 hour, then vacuum concentration.Use the water treatment resistates, leach sedimentary crystallization, wash with water, generate 3.05g (100%) title compound, fusing point: 138-145 ℃.
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carboxylic acid (2-chloroethyl)-acid amides (XXV)
With 1.0g (3.07mmol) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] mixture of benzodiazepine , 25ml anhydrous methylene chloride and 0.62g (5.88mmol) 2-chloroethyl isocyanate concentrates then stirring at room 24 hours.Backflow purifying resistates in ethanol generates 1.25g (94%) title compound, fusing point: 222-223 ℃.
(±)-phenyl (8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -3-carbon sulfenyl)-carbamate (XXVI)
0.37g (3.80mmol) potassium sulfocyanate is dissolved in the 8ml acetone, in mixture, dropwise adds 0.48ml (3.80mmol) phenyl chloroformate in room temperature then.Reaction mixture stirring at room 0.5 hour, was stirred 0.25 hour at 40 ℃ then.Then with ice-water cooling mixture, with 1.04g (3.20mmol) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] the dropwise adding of the solution of [2,3] benzodiazepine in 15ml acetone through 0.5 hour.Stir after 0.5 hour, evaporate most of solvent, use the water treatment resistates, filtering for crystallizing washes with water, generates 1.73g (90%) title compound.Fusing point: 160 ℃.
(±)-1-methyl-3-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl }-urea (XXVII)
XVI is dissolved in the 8ml dimethyl formamide with 1.57g (3.11mmol) compounds X, in the solution of this ice-cooled stirring, dropwise adds 0.35ml (4.04mmol) 40% aqueous methylamine solution.Stir after 2 hours, mixture is poured in the water, leach sedimentary crystallization, wash with water, generate the 1.56g crude product, its recrystallization in ethanol.Productive rate: 1.01g (73%).Fusing point: 192-193 ℃.
Compounds X XVIII and XXIX have been synthesized similarly.
(±)-1-cyclopropyl-3-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl }-urea (XXVIII)
Fusing point: 281-283 ℃ (ethyl acetate). productive rate: 80%
(±)-1-ethyl-3-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl }-urea (XXIX)
Fusing point: 176-177 ℃ (methyl alcohol). productive rate: 73%.
(±)-1-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl }-4-methyl-Urea,amino-(XXX)
In the solution of 0.40g (1.0mmol) compounds X VIII in the 15ml chloroform that stirs, add 0.07ml (1.2mmol) methyl isocyanate.After 1 hour, with sodium hydrogen carbonate solution and water washing reaction mixture, after concentrating, the solids that obtains by backflow purifying in ethanol.Target product is 0.36g, productive rate: 88%.Fusing point: 200 ℃.
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (XXXI)
Based on document (Ling etc., J.Chem.Soc.Perkin Trans.
1: 1423 (1995)) and british patent specification No.2,311,779 described methods have prepared title compound.
Fusing point: 159-160 ℃ of (ethanol) .[α]
D:+172 ° of (c=1; CHCl
3).
(R)-and 7-(tert-butoxycarbonyl)-8-methyl-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (XXXII)
According to document (Anderson etc., J.Am.Chem.Soc.
117: 12358 (1995)) described synthetic method, remove the external application tert-butyl carbazate and replaced acethydrazide, prepared compound.
Fusing point: 168-169 ℃ of (Virahol) .[α]
D:-444 ° of (c=0.6; CHCl
3).
Embodiment 1
(±)-8-methyl-5-(4-nitrophenyl)-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 1.00g (2.60mmol) raw material I, 2.54g (12.89mmol) bromoacetaldehyde diethyl acetal and 10ml dimethyl formamide was stirred 40 minutes at 80 ℃.The dilute with water reaction mixture with the crude product recrystallization in ethanol that obtains, generates 0.85g (80%) title compound then.Fusing point: 145-150 ℃.
Embodiment 2
(R)-and 8-methyl-5-(4-nitrophenyl)-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, obtained title compound from raw material II.Fusing point: 108-110 ℃, productive rate: 89%, [α]
D:+514 ° of (c=0.5; CHCl
3)
Embodiment 3
(S)-and 8-methyl-5-(4-nitrophenyl)-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, I has obtained title compound from raw material II.Fusing point: 114-116 ℃, productive rate: 83%, [α]
D:-522 ° of (c=0.6; CHCl
3)
Embodiment 4
(±)-8-methyl-7-(4-methyl-thiazol-2-yl)-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 0.76g (1.98mmol) raw material I, 1.10g (11.88mmol) monochloroacetone and 15ml dimethyl formamide was stirred 40 minutes at 80-90 ℃.The dilute with water reaction mixture leaches sedimentary crystallization then, drying, and carry out purifying by in ethanol, refluxing, generate 0.69g (82%) title compound; Fusing point: 188-189 ℃.
Embodiment 5
(±)-8-methyl-7-(5-methyl-thiazol-2-yl)-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 1.50g (3.90mmol) raw material I, 3.57g (19.50mmol) 2-bromo propionic aldehyde dimethylacetal and 15ml dimethyl formamide was stirred 1.5 hours at 90 ℃.The dilute with water reaction mixture uses silica gel (MN Kieselgel 60 then; Macherey-Nagel, D ü ren, Germany) as sorbent material, the mixture of toluene-ethyl acetate (16: 1) by the crude product of column chromatography purifying gained, generates 1.08g (66%) title compound as eluent; Fusing point: 193-195 ℃.
Embodiment 6
(±)-7-(4,5-dimethyl-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9- Dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 0.60g (1.56mmol) raw material I, 1.02g (9.57mmol) 3-chloro-2-butanone and 8ml dimethyl formamide was stirred 3 hours at 90 ℃.After the cooling, leach sedimentary crystallization, drying, and carry out purifying by recrystallization in dimethyl formamide and water, generate 0.49g (76%) title compound; Fusing point:>260 ℃ (dec.).
Embodiment 7
(±)-8-methyl-5-(4-nitrophenyl)-7-(4-phenyl-thiazol-2-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 0.45g (1.17mmol) raw material I, 0.35g (1.76mmol) phenacyl bromide and 7ml dimethyl formamide was stirred 30 minutes at 80 ℃.After the cooling, leach sedimentary crystallization, use washing with alcohol, and dry, generate 0.50g (88%) title compound; Fusing point:>260 ℃ (dec.).
Embodiment 8
(±)-7-(4-ethoxy carbonyl-thiazol-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 0.45g (1.17mmol) raw material I, 0.46g (2.36mmol) ethyl bromide acetone and 7ml dimethyl formamide was stirred 30 minutes at 80 ℃.After the cooling, leach sedimentary crystallization, use washing with alcohol, and dry, generate 0.41g (85%) title compound; Fusing point: 242-243 ℃.
Embodiment 9
(±)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-two Chloro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 1.00g (2.6mmol) raw material I, 2.13g (10.40mmol) 2-bromoethyl amine hydrobromate and 10ml dimethyl formamide was stirred 4 hours at 90-100 ℃.Behind the dilute with water, leach sedimentary crystallization, be dissolved in the methylene dichloride, and with the washing of 10% sodium hydrogen carbonate solution several times.After the drying, use silica gel (MN Kieselgel 60) as sorbent material, the mixture of hexane-ethyl acetate (1: 1) by the column chromatography purified product, generates 0.80g (75%) title compound as eluent; Fusing point: 185-187 ℃.
Embodiment 10
(R)-and 7-(4,5-dihydro-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 9 described methods, obtained title compound from raw material II.
Fusing point: 118-124 ℃.Productive rate: 73%, [α]
D:+575 ° of (c=0.4; CHCl
3).
Embodiment 11
(S)-and 7-(4,5-dihydro-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 9 described methods, I has obtained title compound from raw material II.
Fusing point: 120-125 ℃.Productive rate: 71%.[α]
D:-594 ° of (c=0.4; CHCl
3).
Embodiment 12
(±)-7-(4,5-dihydro-4-oxo-thiazol-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 1.00g (2.6mmol) raw material I, 1.19g (7.78mmol) monobromo-acetic acid methyl esters and 10ml dimethyl formamide was stirred 1 hour at 80-90 ℃.Behind the dilute with water, the crude product by backflow purifying in methyl alcohol obtains generates 1.00g (91%) title compound; Fusing point: 218-220 ℃.
Embodiment 13
(±)-7-(4,5-dihydro-5-methyl-4-oxo-thiazol-2-yl)-8-methyl-5-(4-nitre The base phenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
The mixture of 1.00g (2.60mmol) raw material I, 0.94g (5.19mmol) 2-ethyl bromide and 10ml dimethyl formamide was stirred 2 hours at 80-90 ℃.Behind the dilute with water, the crude product by backflow purifying in 15ml ethanol obtains generates 1.08g (95%) title compound; Fusing point: 213-214 ℃.
Embodiment 14
(±)-7-(5,6-dihydro-4-oxo-4H-1,3-thiazine-2-yl)-8-methyl-5-(4-nitre The base phenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
The mixture of 2.00g (5.20mmol) raw material I, 1.89g (10.44mmol) 3-ethyl bromide and 20ml dimethyl formamide was stirred 3 hours at 80-90 ℃.With 25% sodium chloride solution diluted reaction mixture, use dichloromethane extraction.Dry and concentrate after, use silica gel (MN Kieselgel 60) as the mixture of sorbent material, ethyl acetate-methyl alcohol (2: 1) as eluent, by column chromatography purifying crude product, generate 1.34g (59%) title compound;
Fusing point: 220-221 ℃.
Embodiment 15
5-(4-nitrophenyl)-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, obtained title compound from raw material VIII and bromoacetaldehyde diethyl acetal.Fusing point: 203-215 ℃.Productive rate: 77%.
Embodiment 16
(±)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(2-thiazolyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, IV has obtained title compound from raw material.Fusing point: 171-175 ℃.Productive rate: 46%.
Embodiment 17
(±)-8-methyl-5-phenyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, VII has obtained title compound from raw material.Fusing point: 180-184 ℃.Productive rate: 51%.
Embodiment 18
(±)-7-bromo-4-methyl-8-methoxyl group-1-(4-nitrophenyl)-3-(2-thiazole
Base)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 1 described method, X has obtained title compound from raw material.Fusing point: 184-190 ℃.Productive rate: 54%.
Embodiment 19
(±)-8-chloro-4-methyl isophthalic acid-(4-nitrophenyl)-3-(2-thiazolyl)-4, the 5-dihydro
-3H-[2,3] benzodiazepine
According to embodiment 1 described method, V has obtained title compound from raw material.Fusing point: 213-216 ℃.Productive rate: 67%.
Embodiment 20
(±)-8-chloro-4-methyl-3-(4-methyl-thiazol-2-yl)-1-(4-nitrophenyl)-4,5-
Dihydro-3H-[2,3] benzodiazepine
According to embodiment 4 described methods, V has obtained title compound from raw material.Fusing point: 209-216 ℃.Productive rate: 94%.
Embodiment 21
(±)-3-(4,5-dihydro-thiazol-2-yl)-8-chloro-4-methyl isophthalic acid-(4-oil of mirbane
Base)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 9 described methods, V has obtained title compound from raw material.Fusing point: 225-227 ℃.Productive rate: 69%.
Embodiment 22
(±)-3-(4,5-dihydro-3-oxo-thiazol-2-yl)-8-chloro-4-methyl isophthalic acid-(4-nitro
Phenyl)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 12 described methods, V has obtained title compound from raw material.Fusing point: 226-228 ℃.Productive rate: 96%.
Embodiment 23
(±)-7,8-two chloro-4-methyl-3-(4-methyl-thiazol-2-yl)-1-(4-oil of mirbaneBase)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 4 described methods, VI has obtained title compound from raw material.Fusing point: 240-242 ℃.Productive rate: 77%.
Embodiment 24
(±)-7-(4, the 5-dihydro-Evil
Azoles-2-yl)-and 8-methyl-5-(4-nitrophenyl)-8,9-two Hydrogen-7H-1,3-Between the dihydro heterocyclic pentene also
[4,5-h] [2,3] benzodiazepine
The mixture of 1.43g (3.32mmol) raw material XXV, 1.38g (9.98mmol) Anhydrous potassium carbonate, 0.24g (1.60mmol) sodium iodide and 24ml dimethyl formamide was stirred 4 hours at 100-110 ℃.Dilute with water mixture then, the sedimentary crude product of recrystallization in ethanol generates 1.00g (76%) title compound; Fusing point: 194-196 ℃.
Embodiment 25
(±)-8-methyl-5-(4-nitrophenyl)-7-(1,3,4-thiadiazoles-2-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of the hydrochloric acid of 0.57g (1.43mmol) raw material XVIII, 6ml triethyl orthoformate and catalytic amount was stirred 1 hour at 80 ℃.After the cooling, leach sedimentary crystallization, use washing with alcohol, and dry, generate 0.45g (77%) title compound; Fusing point: 212-213 ℃.
Embodiment 26
(R)-and 8-methyl-5-(4-nitrophenyl)-7-(1,3,4-thiadiazoles-2-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 25 described methods, XIX has obtained title compound from raw material.Fusing point: 144-147 ℃ (alcohol-water). productive rate: 88%, [α]
D:+428 ° of (c=0.2; CHCl
3)
Embodiment 27
(±)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
In the mixture of the 1.0g of ice-cooled stirring (2.50mmol) raw material XVIII, 35ml methylene dichloride, 0.40ml (2.75mmol) triethylamine, added 0.22ml (2.80mmol) Acetyl Chloride 98Min..The solution that obtains was like this placed 16 hours in room temperature, added the 0.6g tosic acid then, mixture was stirred 2 hours at 40 ℃.Use sodium hydrogen carbonate solution and water washing reaction mixture to neutral then, drying, and concentrate.Handle crude product with methyl alcohol, recrystallization in ethanol generates 0.99g (91%) title compound then.Fusing point: 213-215 ℃.
Embodiment 28
(R)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Method A.
According to embodiment 27 described methods, by carrying out acidylate with diacetyl oxide, XIX has obtained title compound from raw material.Use silica gel (MN Kieselgel 60) as the mixture of sorbent material, normal hexane-ethyl acetate (1: 1) as eluent, the crude product that obtains by the column chromatography purifying.Concentrate contain the fraction of title compound after, handle resistates with isopropyl ether, generate 0.95g solid foam (polymorphic form). productive rate: 89%.
Method B.
In the solution of 4.04g (10.0mmol) raw material XII, 3ml dimethyl formamide, 1.40ml (10.0mmol) triethylamine and 0.06g (0.5mmol) 4-dimethylaminopyridine, add 1.48g (20.0mmol) acethydrazide.Reaction mixture was stirred 5 hours at 50 ℃, and dilute with water leaches sedimentary crystallization, and washes with water then.According to it
1The H-NMR spectrum, the 4.5g that obtains like this (R)-N '-{ 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl also }-acethydrazide is the mixture of rotational isomer.(mixture that uses normal hexane-ethyl acetate (1: 1) is as eluent, by the column chromatography purifying sample of analyzing, and with the crystallization of 0.5mol ethyl acetate, fusing point: 118 ℃).
Intermediate upward adds the 0.75ml concentrated hydrochloric acid in 50ml alcoholic acid suspension, the solution that obtains was like this refluxed 2 hours.Concentrate and, obtained the 4.2g crude product with after the water treatment.Use silica gel (MN Kieselgel 60) as the mixture of sorbent material, normal hexane-ethyl acetate as eluent, carried out purifying by column chromatography, and 60 ℃ of vacuum-dryings, generate fusing point and be 101-102 ℃ title compound.[α]
D:+453°(c=0.5;CHCl
3).
According to embodiment 27 described methods, use suitable acyl chlorides, obtained the compound of embodiment 29-34.
Embodiment 29
(±)-7-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 142-145 ℃; Productive rate: 49%.
Embodiment 30
(±)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 163-164 ℃; Productive rate: 84%.
Embodiment 31
(R)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 105 ℃; Productive rate: 63%.[α]
D:+418 ° of (c=0.5; CHCl
3).
Embodiment 32
(±)-8-methyl-5-(4-nitrophenyl)-7-(5-Trifluoromethyl-1,3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 184-185 ℃; Productive rate: 67%.
Embodiment 33
(±)-8-methyl-5-(4-nitrophenyl)-7-(5-phenyl-1,3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 210-212 ℃; Productive rate: 56%.
Embodiment 34
(±)-7-(5-chloromethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 210-211 ℃; Productive rate: 64%.
Embodiment 35
(±)-7-(5-cyclopropyl aminomethyl-1,2,3,4-thiadiazoles-2-yl)-8-methyl-5-(4- Nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo two Azatropylidene
With 5ml dimethyl formamide, 0.44g (0.96mmol) (±)-7-(5-chloromethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine (embodiment 34) and 0.37ml (5.31mmol) cyclopropylamine stirred 1 hour at 70-80 ℃.Reaction mixture is poured in 20% sodium chloride solution then, sedimentary crude product is extracted in the ethyl acetate.Wash solution with water, drying after the evaporation, generates the title compound of 0.39g (85%) solid foam shape.
Embodiment 36
(±)-8-chloro-4-methyl isophthalic acid-(4-nitrophenyl)-3-(1,3,4-thiadiazoles-2-
Base)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 25 described methods, XX has obtained title compound from raw material.Fusing point: 188 ℃; Productive rate: 86%
Embodiment 37
(±)-8-chloro-4-methyl-3-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-1-(4-oil of mirbane
Base)-4,5-dihydro-3H-[2,3] benzodiazepine
According to embodiment 27 described methods, XX has obtained title compound from raw material.Fusing point: 162-164 ℃; Productive rate: 52%.
Embodiment 38
(±)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(5-methyl isophthalic acid, 3,4-thiadiazoles -2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
According to the described process of the method A of embodiment 28, XXII has obtained title compound from raw material.
Fusing point: 228-240 ℃; Productive rate: 74%.
Embodiment 39
(±)-8-methyl-5-(4-methyl-3-nitro phenyl)-7-(5-methyl isophthalic acid, 3,4-thiadiazoles -5-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
According to the described process of the method B of embodiment 28, XV has obtained title compound from raw material.
Fusing point: 220 ℃ (ethanol); Productive rate: 57%.
Embodiment 40
(±)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-5-(3-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to the described process of the method B of embodiment 28, XIII has obtained title compound from raw material.
Fusing point: 118-119 ℃; Productive rate: 67%.
Embodiment 41
(±)-7-bromo-4-methyl-3-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8-methoxyl group
-1-(4-nitrophenyl)-4,5-dihydro-3H-[2,3] benzodiazepine
According to the described process of the method A of embodiment 28, XXI has obtained title compound from raw material.
Fusing point: 229-233 ℃; Productive rate: 76%.
Embodiment 42
(±)-8-methyl-7-(5-methyl-6H-1,3,4-thiadiazine-2-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
With the mixture of 1.00g (2.50mmol) raw material XVIII, 20ml dimethyl formamide and 0.57g (6.16mmol) monochloroacetone stirring at room 2 hours.Behind the dilute with water, leach sedimentary crystallization, the purifying that refluxes in ethyl acetate generates 0.73g (67%) title compound; Fusing point: 203-204 ℃.
Embodiment 43
(±)-7-(5,6-dihydro-5-oxo-4H-1,3,4-thiadiazine-2-yl)-8-methyl -5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] Benzodiazepine
The mixture of 1.00g (2.50mmol) raw material XVIII, 20ml dimethyl formamide and 0.94g (6.14mmol) monobromo-acetic acid methyl esters was stirred 1.5 hours at 70 ℃.Behind the dilute with water, leach sedimentary crystallization, the purifying that refluxes in ethyl acetate generates 0.41g (37%) title compound; Fusing point: 294-295 ℃ (dec.).
Embodiment 44
(±)-8-methyl-5-(4-nitrophenyl)-7-(5-oxo-4,5-dihydro-1,3,4-thiophene two Azoles-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo two Azatropylidene
At 80 ℃ of mixtures that stir 2.14g (4.69mmol) raw material XXX and 122ml concentrated hydrochloric acid.From starting soln, be settled out solids.With reaction mixture be concentrated to its volume pact half, with the dilution of 40ml water, transfer to alkalescence with sodium hydrogen carbonate solution.Leach sedimentary product, wash with water, generate 1.40g (70%) title compound.Fusing point: 288 ℃.
Embodiment 45
(R)-8-methyl-5-(4-nitrophenyl)-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-
Base)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
With the 2.2g (5.15mmol) that stirs (R)-N '-(8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl)-mixture of acethydrazide (intermediate of the method B of embodiment 28), 44ml ethanol and 1.72g (5.39mmol) mercuric acetate (II) refluxed 2 hours.Be dissolved in the methylene dichloride concentrating the resistates that obtains, and filter by the neutral alumina column.Behind the washing column, concentrated filtrate, use silica gel (MN Kieselgel 60) as the mixture of sorbent material, normal hexane-ethyl acetate (1: 2.5) as eluent, by column chromatography purifying resistates, generate 1.07g (51%) title compound.In ethanol behind the recrystallization, fusing point: 202-204 ℃.[α]:-249°(c=0.22;CHCl
3).
Embodiment 46
(±)-8-methyl-7-(2-methyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-5- Base)-and 5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
In the solution of the 0.44g of ice-cooled stirring (1.0mmol) raw material XXVI I in the 8ml chloroform, add the solution of 0.19g (1.2mmol) bromine in the 3ml chloroform.0.5 after hour, with 15ml chloroform diluted reaction mixture, and with sodium hydrogen carbonate solution and water washing.Stir the concentrated resistates that obtains with methyl alcohol, and filter, generate 0.36g (82%) title compound.In ethyl acetate behind the recrystallization, fusing point: 296 ℃.
From raw material XXVIII and XXIX, obtained the compound of embodiment 47 and 48 similarly respectively.
Embodiment 47
(±)-7-(2-cyclopropyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-5-yl)-8-first Base-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 246-247 ℃ (ethyl acetate), productive rate: 64%.
Embodiment 48
(±)-7-(2-ethyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-5-yl)-8-methyl -5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] Benzodiazepine
Fusing point: 250-256 ℃, productive rate: 60%.
Embodiment 49
(±)-7-(4-carboxyl thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Stir 9ml ethanol, 0.85g (1.89mmol) (±)-7-(4-ethoxy carbonyl-thiazol-2-yl)-8-methyl-5-(4-nitrophenyl)-8 at 90 ℃, 9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine (embodiment 8) and 7ml 1N sodium hydroxide solution.After the cooling, use the acetate acidifying, dilute with water, and leach sedimentary crystallization, and wash with water and drying, generate 0.78g (98%) title compound; Fusing point:>260 ℃.
Embodiment 50
(±)-8-methyl-5-(4-nitrophenyl)-7-(5-tetrazyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 0.60g (1.70mmol) raw material XXIII, 3ml dimethyl formamide, 0.12g (1.87mmol) sodiumazide and 0.10g (1.87mmol) ammonium chloride was stirred 30 minutes at 140 ℃.Dilute with water refrigerative reaction mixture leaches sedimentary crystallization.Use silica gel (MN Kieselgel 60) as the mixture of sorbent material, chloroform-methanol (99: 1) as eluent, by the column chromatography purifying product that obtains like this, generate 0.68g (54%) title compound; Fusing point: 263-264 ℃.
Embodiment 51
(±)-8-methyl-5-(4-nitrophenyl)-7-(1,2,4-oxadiazole-3-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Under the situation that has 0.05ml 36% hydrochloric acid, the mixture of 1.50g (3.91mmol) raw material XXIV and 15ml triethyl orthoformate was stirred 30 minutes at 110 ℃, then vacuum concentration.Stir resistates with water, leach sedimentary crystallization, wash with water, and in 2-methyl cellosolve recrystallization, generate 1.15g (75%) title compound; Fusing point: 190-196 ℃.
Embodiment 52
(±)-8-methyl-7-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
The mixture of 3.0g (7.82mmo l) raw material XXIV and 15ml diacetyl oxide was stirred 1 hour at 110 ℃, after cooling, dilute with water, and use dichloromethane extraction.Concentrate organic layer, use silica gel (MN Kieselgel 60) as the mixture of sorbent material, normal hexane-ethyl acetate (2: 1) as eluent, by the column chromatography purifying resistates, generate 1.58g (50%) title compound; Fusing point: 191-200 ℃.
Embodiment 53
(±)-8-methyl-7-(2-methylthiazol-4-yl)-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(±)-7-bromo ethanoyl-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
The mixture of 4.80g (14.7mmol) raw material I, 24ml dimethyl formamide, 2.16g (15.5mmol) monobromo-acetic acid and 4.56g (22mmol) dicyclohexyl carbodiimide was stirred 20 hours.Filter reaction mixture, concentrated filtrate.Resistates is absorbed in the ethyl acetate, washes with water, concentrate, recrystallization in ethanol generates 4.83g (73%) title compound; Fusing point: 183-186 ℃.
Step B
The product that will obtain in steps A is dissolved in the 45ml dimethyl formamide, behind adding 4.96g (65mmol) thioacetamide, mixture stirred 1 hour at 80 ℃, and cooling then, and pour in the water.Leach sedimentary crude product, wash with water, use silica gel (MNKieselgel 60) as the mixture of sorbent material, hexane-ethyl acetate (9: 1) as eluent, by the column chromatography purifying, generate 1.67g (37%) title compound; Fusing point: 178-190 ℃.
Embodiment 54
(±)-8-methyl-5-(4-nitrophenyl)-7-(2-pyrimidyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
The 1-{6-[(4-nitrophenyl)-(pyrimidine-2-base-hydrazono-)-methyl]-phendioxin, 3-dioxole-5-yl }-propane-2-alcohol
With 3.29g (9.99mmol) (±)-7-methyl-5-(4-nitrophenyl)-7 that stirs, 8-dihydro-5H-[1,3] dioxole also [4,5-g] heterochromatic full-mixture of 5-alcohol, 40ml ethyl acetate and 1.0ml (1.15mmol) perchloric acid refluxed 1 hour.After the cooling, leach sedimentary (±)-7-methyl-5-(4-nitrophenyl)-7,8-dihydro-[1,3] dioxole also [4,5-g] heterochromatic alkene-6-base perchlorate, stirred 2 hours with the 1.6g in the 50ml Virahol (14.55mmol) 2-diazanyl pyrimidine at reflux temperature, concentrate then.Resistates is dissolved in the methylene dichloride, washes with water for several times.After the dry and evaporation, use silica gel (MN Kieselgel 60) as the mixture of sorbent material, toluene-ethyl acetate (0.1: 4) as eluent, by column chromatography purifying crude product, generate 2.71g (64%) title compound; Fusing point: 125-127 ℃.
Step B
The 1-{6-[(4-nitrophenyl)-(pyrimidine-2-base-hydrazono-)-methyl]-phendioxin, 3-dioxole-5-yl }-propane-2-alcohol methanesulfonates
The compound dissolution that 2.35g (5.58mmol) is prepared in steps A is in the 50ml anhydrous methylene chloride.Solution is cooled to 0 ℃, add 2.1ml (15.07mmol) triethylamine after, 0.87ml (11.22mmol) methylsulfonyl chloride was added through 20 minutes, then with mixture stirring at room 3 hours.After washing with water, drying, and concentrate, generate 2.69g (54%) title compound, as intermediate; Fusing point: 122-124 ℃.
Step C
1: 1 the methylene chloride-methanol mixture of compound, 60ml that 3.13g (6.27mmol) is prepared in step B and the mixture of 0.52ml (6.90mmol) 50% sodium hydroxide solution were stirring at room 1.5 hours.After the filtration, concentrated reaction mixture is used the water treatment resistates, and recrystallization in containing 3 times of dimethyl formamides of 10% water generates 1.96g (77%) title compound; Fusing point: 261-263 ℃.
Embodiment 55
(±)-7-(3-chlorine pyridazine-6-yl)-8-methyl-5-(4-nitrophenyl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
1-{6-[(6-chlorine pyridazine-3-yl)-hydrazono--(4-nitrophenyl)-methyl]-(phendioxin, 3-dioxole-5-yl) }-propane-2-alcohol
With 2.00g (6.07mmol) (±)-7-methyl-5-(4-nitrophenyl)-7 that stirs, 8-dihydro-5H-[1,3] dioxole also [4,5-g] heterochromatic full-mixture of 5-alcohol, 32ml Virahol, 0.3ml hydrochloric acid and 1.04g (7.28mmol) 4-diazanyl-6-chlorine pyridazine refluxed 3 hours.Behind the dilute with water, leach sedimentary crystallization, drying, elder generation's recrystallization in ethyl acetate, recrystallization in the dimethyl formamide that contains 10% water generates 1.53g (55%) title compound then; Fusing point: 135-137 ℃.
Step B
The mixture of compound, 10ml dimethyl formamide and 0.34g (1.30mmol) triphenylphosphine that 0.3g (0.66mmol) is prepared in steps A was stirring at room 5 minutes, add 0.20ml (1.27mmol) diethylazodicarboxylate then, and continue to stir 24 hours.With after the sodium chloride solution dilution, leach sedimentary product, drying, and use silica gel (MNKieselgel 60) as the mixture of sorbent material, chloroform-methanol (99: 1) as eluent, by the column chromatography purifying.By refluxing in ethanol, crystallization generates 0.12g (42%) title compound through concentrating the resistates that obtains; Fusing point: 254-255 ℃.
Embodiment 56
(±)-8-methyl-5-(4-nitrophenyl)-7-(1H (2H)-1,2,4-triazole-3- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-S-methyl-sulfo-azomethine hydrochlorate also
Existing under the situation of salt of wormwood, in room temperature, the raw material I from dimethyl formamide has obtained title compound with methyl iodide.Fusing point: 191-192 ℃, productive rate: 94%.
Step B
Under the situation of the tosic acid that has catalytic amount, the mixture of compound, 110ml 2-methyl cellosolve and 4.50g (74.93mmol) formyl hydrazine that 3.0g (7.53mmol) is obtained in steps A stirred 16 hours at 110 ℃.Handle the concentrated resistates that obtains with 10% sodium carbonate solution, the crude product that filtration obtains, dry, and use silica gel (MN Kieselgel60) as the mixture of sorbent material, hexane-ethyl acetate (1: 2) as eluent, by the column chromatography purifying, generate 1.86g (63%) title compound; Fusing point: 154-156 ℃.
Embodiment 57
(±)-8-methyl-7-(5-methyl-2 (1) H-1,2,4-triazole-3-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Under the situation of the tosic acid that has catalytic amount, with 15ml 2-methyl cellosolve, 0.41g (1.03mmol) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine -7-S-methyl-sulfo-azomethine hydrochlorate (steps A of embodiment 56) and 0.35g (4.68mmo l) acethydrazide stirred 16 hours at 110 ℃.Handle the concentrated resistates that obtains with 10% sodium carbonate solution, the crude product that filtration obtains, dry, and use silica gel (MN Kieselgel 60) as the mixture of sorbent material, hexane-ethyl acetate (1: 2) as eluent, by the column chromatography purifying, generate 0.32g (78%) title compound; Fusing point: 144-147 ℃ (the solid foam shape).
Embodiment 58
(±)-7-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (isomer I) and (±)-7-(2,5-dimethyl-2H-1,2,4-triazole-3-yl)-8-methyl -5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] Benzodiazepine (isomer II)
With 0.57g (5.08mmol) potassium tert.-butoxide, 2.05g (5.04mmol) (±)-8-methyl-7-(5-methyl-2 (1) H-1,2,4-triazole-3-yl)-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine (embodiment 57), 40ml tetrahydrofuran (THF) and 0.32ml (5.14mmol) methyl iodide is stirring at room 16 hours.The dilute with water reaction mixture is used ethyl acetate extraction then, dry organic layer, and concentrate.Use silica gel (MN Kieselgel 60) as sorbent material, ethyl acetate as eluent, by 2 kinds of products that form in the column chromatography separating reaction.At first obtained having R
F: 0.55 isomer II, it refluxes in ethanol, generates 0.30g (14%), fusing point: 185-187 ℃.Collect then and have R
F: 0.26 isomer I, after it refluxes in ethanol, the 0.67g that weighs (32%), fusing point: 193-195 ℃.
Embodiment 59
(±)-8-methyl-7-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine (isomer I) and (±)-8-methyl-7-(2-methyl-2H-1,2,4-triazole-3-yl)-5-(4- Nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo two Azatropylidene (isomer II)
With 0.41g (3.65mmol) potassium tert.-butoxide, 1.4g (3.57mmol) (±)-8-methyl-5-(4-nitrophenyl)-7-(1H (2H)-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] mixture of [2,3] benzodiazepine (embodiment 56), 35ml tetrahydrofuran (THF) and 0.23ml (3.69mmol) methyl iodide is stirring at room 16 hours.Behind the dilute with water, use the ethyl acetate extraction reaction mixture, dry organic layer, and concentrate.Use silica gel (MN Kieselgel 60) as sorbent material, ethyl acetate as eluent, by 2 kinds of products that form in the column chromatography separating reaction.Has R
F: the heavy 0.37g of 0.22 isomer I, productive rate: fusing point 26%: 115-117 ℃.Has R
F: 0.63 isomer II is 0.35g, productive rate: fusing point 24%: 92-94 ℃.
Embodiment 60-119
The general operation of the nitro of the compound that obtains among the embodiment above the reduction.
Method A
The 2.0mmol nitro-compound is dissolved in the mixture of methyl alcohol-methylene dichloride, behind adding 6-10mmol 85-98% hydrazine hydrate and the 0.1-2g RaNi catalyzer, mixture was stirred 1-5 hour at 20-40 ℃.Behind the filtering catalyst, concentrated filtrate is used the water treatment resistates, and leaches product.
Method B
With 5.5g RaNi catalyzer pre-hydrogenation in methyl alcohol-dichloromethane mixture of 2: 1 of 250ml, then the 20.0mmol nitro-compound is added in the above-mentioned solvent mixture of 250ml the mixture that hydrogenation obtains like this under barometric point.Behind the filtering catalyst, concentrated filtrate is used the water treatment resistates, filtration product, and washing is also dry.
Method C
The mixture of the 1.82mmol nitro-compound, 30ml ethanol and 2.46g (10.91mmol) tin chloride (II) dihydrate that stir was refluxed 3 hours.Concentrated reaction mixture adds sodium bicarbonate aqueous solution and ethyl acetate in the resistates then.After the separation, use the ethyl acetate extraction water,, and concentrate with the organic layer that the sodium chloride solution washing merges, drying.If desired, by column chromatography or recrystallization purifying resistates.
Method D
The 3.4mmol nitro-compound is dissolved in the mixture of 35ml methyl alcohol-methylene dichloride (1: 1), adds 0.4g 10% carried by active carbon palladium catalyst and 0.47g salt of wormwood, under the situation that has 1ml water, the mixture that hydrogenation obtains like this.After finishing reaction, leach catalyzer, concentrated filtrate is used the water treatment resistates, and filters.
Method E
The 4.0mmol nitro-compound is dissolved into 48ml contains in the methyl alcohol of 5% water, behind adding 0.20g catalyzer 10% activated carbon-carried palladium, dropwise add the 3.5 normal dense potassium formiate aqueous solution, stir the mixture at said temperature in room temperature.After finishing reaction, leach catalyzer, concentrated filtrate is used the water treatment resistates, and filters.
Table 10.
Contain 2 of aminophenyl group, 3-benzodiazepine
(except as otherwise noted, at the 250MHz record
1H NMR spectrum)
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
60 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 187-190 | 78 |
Method A | 1H NMR(CDCl 3)δ1.32(3H,d,6.5Hz),2.78(1H,dd,14.0Hz,9.7Hz), 2.97(1H,dd,14.0Hz,4.9Hz),3.80(2H,br),5.26(1H,m),5.98(2H, m),6.65(1H,s),6.67(1H,d,4.0Hz),6.73(2H,dm),6.80(1H,s), 7.37(1H,d,4.0Hz),7.55(2H,dm) MS:EI(70eV):[M] +.:378,m/z:363,279,278,253,252 | ||
61 | (R)-5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 125-130 | 84 -578° (c=1,CHCl 3) |
Method A | 1H NMR(CDCl 3)δ1.29(3H,d,6.5Hz),2.77(1H,dd,14.0Hz,9.7Hz), 3.00(1H,dd,14.0Hz,4.9Hz),3.92(2H,br),5.23(1H,m),5.98(2H, m),6.62(1H,d,4.0Hz),6.65(1H,s),6.72(2H,dm),6.80(1H,s), |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
7.32(1H,d,4.0Hz),7.55(2H,dm) | |||
62 | (S)-5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 124-128 | 94 +546° (c=0.34,CHCl 3) |
Method A | 1H NMR(DMSO-d 6)δ1.15(3H,d,6.5Hz),2.60(1H,dd,13.6Hz,10.5 Hz),2.94(1H,dd,13.6Hz,4.8Hz),4.99(1H,m),5.72(2H,br),6.03 (2H,m),6.60(2H,dm),6.62(1H,s),6.81(1H,d,4.0Hz),7.04(1H, s),7.27(1H,d,4.0Hz),7.55(2H,dm) MS:EI(70eV):[M] +.:378,m/z:377,363,279,278,253,252 CI:[M+H] +:379,[M] +.:378,m/z:363 | ||
63 | (±)-5-(4-aminophenyl)-8-methyl-7-(4-methyl-thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 190-191 (EtOH) | 65 |
Method A | 1H NMR(CDCl 3)δ1.30(3H,d,6.5Hz),2.29(3H,s),2.77(1H,dd,14.0 Hz,10.0Hz),2.92(1H,dd,14.0Hz,5.1Hz),3.94(2H,br),5.27(1H, m),5.97(2H,m),6.20(1H,s),6.53(2H,dm),6.70(1H,s),6.88(1H, s),7.53(2H,dm) | ||
64 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-methyl-thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 165-167 | 47 |
Method A | 1H NMR(DMSO-d 6)δ1.17(3H,d,6.5Hz),2.25(3H,s),2.60(1H,dd, 13.9Hz,10.3Hz),2.94(1H,dd,13.9Hz,5.1Hz),4.95(1H,m),5.70 (2H,br),6.05(2H,dm),6.57(1H,s),6.62(2H,dm),6.93(1H,s), 7.04(1H,s),7.36(2H,dm) | ||
65 | (±)-5-(4-aminophenyl)-8-methyl-7-(4,5-dimethyl-thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 240-242 (EtOH) | 83 |
Method A | 1H NMR(DMSO-d 6)δ1.16(3H,d,6.5Hz),2.06(3H,s),2.13(3H,s), 2.62(1H,dd,14.0Hz,10.0Hz),2.92(1H,dd,14.0Hz,5.0Hz),4.97 (1H,m),5.70(2H,br),6.04(2H,dm),6.60(1H,s),6.62(2H,dm), 7.02(1H,s),7.34(2H,dm) | ||
66 | (±)-5-(4-aminophenyl)-7-(4-phenyl-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 221-223 (EtOH) | 89 |
Method A | 1H NMR(CDCl 3)δ1.29(3H,d,6.5Hz),2.80(1H,dd,14.0Hz,9.4Hz), 3.00(1H,dd,14.0Hz,4.8Hz),3.93(2H,br),5.40(1H,m),5.98(2H, m),6.62(1H,s),6.70(2H,dm),6.78(1H,s),7.29(1H,t),7.39(1H, t),7.50(1H,s),7.57(2H,dm),7.86(2H,d) |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
67 | (±)-5-(4-aminophenyl)-7-(4-ethoxy carbonyl-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 251-252 (EtOH) | 83 |
Method A | 1H NMR(CDCl 3)δ1.29(3H,d,6.5Hz),1.38(3H,t),2.76(1H,dd,14.0 Hz,10.0Hz),2.92(1H,dd,14.0Hz,5.0Hz),3.98(2H,br),4.33(2H, q),5.40(1H,m),6.00(2H,m),6.68(1H,s),6.69(2H,dm),6.82(1H, s),6.86(1H,s),7.51(2H,dm) | ||
68 | (±)-5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 145-150 (EtOH) | 84 |
Method A | 1H NMR(CDCl 3)δ1.21(3H,d,6.5Hz),2.70(1H,dd,14.0Hz,10.0Hz), 2.96(1H,dd,14.0Hz,5.0Hz),3.20(1H,m),3.70(1H,m),3.90(2H, br),4.17(2H,m),5.09(1H,m),5.98(2H,dm),6.60(1H,s),6.66 (2H,dm),6.73(1H,s),7.47(2H,dm) MS:EI(70eV):[M] +.:380,m/z:365,339,279,264,253,252 | ||
69 | (R)-5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 148-150 (EtOH) | 82 -239° (c=0.5,CHCl 3) |
Method A | 1H NMR(DMSO-d 6)δ1.16(3H,d,6.5Hz),2.60(1H,dd,14.0Hz,10.0 Hz),2.90(1H,dd,14.0Hz,4.0Hz),3.25(2H,m),4.00(2H,m),4.82 (1H,m),5.73(2H,br),6.07(2H,dm),6.64(s),6.64(2H,dm),7.02 (1H,s),7.30(2H,dm) MS:EI(70eV):[M] +.:380,m/z:365,339,279,278,264,253,252 CI:[M+H] +:381,[M] +.:380,m/z:279 | ||
70 | (S)-5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 150-152 | 92 +175° (c=0.51,CHCl 3) |
Method A | MS:EI(70eV):[M] +:380,m/z:365,339,279,278,264,253,252 CI:[M+H] +:381,[M] +:380,m/z:279 | ||
71 | (±)-5-(4-aminophenyl)-7-(4,5-dihydro-4-oxo-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 218-220 (EtOH) | 85 |
Method A | 1H NMR(DMSO-d 6)δ1.29(3H,d,6.5Hz),2.61(1H,dd,13.0Hz,12.0 Hz),2.96(1H,dd,13.0Hz,5.0Hz),3.72(2H,m),5.08(1H,m),6.01 (2H,br),6.06(2H,dm),6.60(2H,dm),6.62(1H,s),7.10(1H,s), 7.40(2H,dm) | ||
72 | (±)-5-(4-aminophenyl)-7-(4,5-dihydro-5- | 200-204 | 63 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Methyl-4-oxo-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | (EtOH) | ||
Method A | 1H NMR(DMSO-d 6) δ 1.32 (d) and 1.45 (d, overlapping, diastereomers), 2.60 (1H, dd, 13.0Hz, 12.0Hz), 2.94 (1H, dd, 13.0Hz, 5.0Hz), 3.96 and 4.05 (1H, q), 5.08 (1H, m), 6.0 (2H, br), 6.07 (2H, dm), 6.60 (2H, dm), 6.62 (1H, s), 7.08 (1H, s), 7.40 (2H, dm) MS:EI (70eV): [M] +.:408,m/z:393,279,265,253,252 | ||
73 | (±)-5-(4-aminophenyl)-7-(5,6-dihydro-4-oxo-4H-1,3-thiazine-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 226-228 (EtOH) | 90 |
Method A | 1H NMR(DMSO-d 6)δ1.25(3H,d,6.5Hz),2.35(2H,m),2.57(1H,dd, 13.0Hz,12.0Hz),2.88(1H,dd,13.0Hz,4.0Hz),3.05(2H,m),5.21 (1H,m),5.97(2H,br),6.09(2H,dm),6.60(1H,s),6.62(2H,dm), 7.04(1H,s),7.42(2H,dm) MS:EI(70eV):[M] +.:408,m/z:295,279,253,252 | ||
74 | 5-(4-aminophenyl)-7-(2-thiazolyl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | 200-204 | 52 |
Method A | 1H NMR(DMSO-d 6)δ2.88(2H,t),4.21(2H,t),5.70(2H,s),6.08(2H, s),6.60(1H,s),6.62(2H,dm),6.89(1H,d,4.0Hz),7.08(1H,s), 7.28(1H,d,4.0Hz),7.37(2H,dm) | ||
75 | (±)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 225-227 | 78 |
Method B | MS:EI(70eV):[M] +.:392,m/z:377,293,266 CI:[M+H] +:393,[M] +.:392,m/z:266 | ||
76 | (±)-1-(4-aminophenyl)-4-methyl-8-methoxyl group-3-(2-thiazolyl)-4,5-dihydro-3H-[2,3] benzodiazepine | 105-107 | 57 |
Method D | MS:EI(70eV):[M] +.:364,m/z:349,265,223 CI:[M+H] +:365,[M] +.:364 | ||
77 | (±)-1-(4-aminophenyl)-8-chloro-4-methyl-3-(2-thiazolyl)-4,5-dihydro-3H-[2,3] benzodiazepine | 104-107 | 72 |
Method A | 1H NMR(CDCl 3)δ1.31(3H,d,6.5Hz),2.96(1H,dd,13.0Hz,10.0Hz), 3.10(1H,dd,13.0Hz,5.0Hz),5.35(1H,m),6.68(1H,d,4.0Hz), 6.72(2H,dm),7.21(1H,d,4.0Hz),7.25(1H,d,1.0Hz),7.27(1H, d,7.0Hz),7.34(1H,dd),7.53(2H,dm) | ||
78 | (±)-1-(4-aminophenyl)-8-chloro-4-methyl | 173-175 | 90 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
-3-(4-methyl-thiazol-2-yl)-4,5-dihydro-3H-[2,3] benzodiazepine | |||
Method A | 1H NMR(CDCl 3)δ1.26(3H,d,6.5Hz),2.27(3H,d,1.0Hz),2.81(1H, dd,14.0Hz,9.7Hz),3.02(1H,dd,14.0Hz,5.0Hz),3.95(2H,br), 5.28(1H,m),6.20(1H,q,1.0Hz),6.70(2H,dm),7.17(1H,d,2.2 Hz),7.22(1H,d,8.2Hz),7.33(1H,dd,8.2Hz,2.2Hz),7.51(2H, dm) | ||
79 | (±)-1-(4-aminophenyl)-3-(4,5-dihydro-thiazol-2-yl)-8-chloro-4-methyl-4,5-dihydro-3H-[2,3] benzodiazepine | 213-216 (MeOH) | 79 |
Method A | 1H NMR(DMSO-d 6)δ1.08(3H,d,6.5Hz),2.68(1H,dd,14.0Hz,10.0 Hz),3.06(1H,dd,14.0Hz,5.0Hz),3.20(2H,m),4.02(2H,m),5.68 (2H,s),4.92(1H,m),6.60(2H,dm),7.09(1H,d,1.0Hz),7.28(2H, dm),7.41(1H,d,7.0Hz),7.48(1H,dd) | ||
80 | (±)-(4-(4-aminophenyl)-3-(4,5-dihydro-4-oxo-thiazol-2-yl)-8-chloro-4-methyl-4,5-dihydro-3H-[2,3] benzodiazepine | 226-228 (iPrOH) | 75 |
Method A | 1H NMR(DMSO-d 6)δ1.32(3H,d,6.5Hz),2.68(1H,dd,13.8Hz,12.0 Hz),3.08(1H,dd,13.8Hz,4.8Hz),3.77(2H,m),5.10(1H,m),6.12 (2H,br),6.66(2H,dm),7.17(1H,d,2.0Hz),7.41(2H,dm),7.52 (1H,d,8.0Hz),7.54(1H,dd,8.0Hz,2.0Hz) | ||
81 | (±)-1-(4-aminophenyl)-7,8-two chloro-3-(4-methyl-thiazol-2-yl)-4-methyl-4,5-dihydro-3H-[2,3] benzodiazepine | 182-184 (EtOH) | 48 |
Method A | 1H NMR(CDCl 3)δ1.28(3H,d,6.5Hz),2.30(3H,s),2.80(1H,dd,14.0 Hz,9.6Hz),3.02(1H,dd,14.0Hz,4.9Hz),3.96(2H,br),5.31(1H, m),6.22(1H,q,1.0Hz),6.69(2H,dm),7.28(1H,s),7.39(1H,s), 7.50(2H,dm) | ||
82 | (±)-5-(4-aminophenyl)-7-(4,5-dihydro-Evil azoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 166-167 (EtOH) | 87 |
Method A | 1H NMR(DMSO-d 6)δ1.20(3H,d,6.5Hz),2.31(1H,dd,13.8Hz,12.0 Hz),2.78(1H,dd,13.8Hz,5.8Hz),3.61(2H,m),4.18(2H,m),4.51 (1H,m),5.66(2H,br),6.03(2H,dm),6.51(1H,s),6.53(2H,dm), 6.98(1H,s),7.30(2H,dm) MS:EI(70eV):[M] +.:364,m/z:349,323,279,278,252 CI:[M+H] +:365,[M] +.:364 | ||
83 | (±)-5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 192-194 (50%EtOH-H 2O) | 77 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Method A | 1H NMR(DMSO-d 6)δ1.20(3H,d,6.5Hz),2.62(1H,dd,13.9Hz,10.8 Hz),2.99(1H,dd,13.9Hz,5.2Hz),5.01(1H,m),5.78(2H,br),6.03 (2H,dm),6.58(1H,s),6.60(2H,dm),7.07(1H,s),7.32(2H,dm,) | ||
84 | (R)-5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 219-220 (ethyl formate) | 67 -490° (c=0.9,CHCl 3) |
Method C | 1H NMR(CDCl 3)δ1.33(3H,d,6.5Hz),2.80(1H,dd,14.0Hz,9.9Hz), 2.97(1H,dd,14.0Hz,5.0Hz),4.02(2H,br),5.30(1H,m),5.98(2H, dm),6.65(1H,s),6.68(2H,dm),6.80(1H,s),7.51(2H,dm,),8.50 (1H,s) | ||
85 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 143-148 | 89 |
Method A | 1H NMR(CDCl 3)δ1.32(3H,d,6.5Hz),2.56(3H,s),2.76(1H,dd,14.0 Hz,10.0Hz),2.93(1H,dd,14.0Hz,5.0Hz),4.00(2H,br),5.19(1H, m),5.98(2H,dm),6.64(1H,s),6.70(2H,dm),6.79(1H,s),7.48 (2H,dm,) MS:EI(70eV):[M] +.:393,m/z:378,279,278,253,252 CI:[M+H] +:394,[M] +.:393,m/z:252 | ||
86 | (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 168-170 (50%EtOH-H 2O) | 78 -482° (c=0.5,CHCl 3) |
Method B.C | 1H NMR(DMSO-d 6)δ1.23(3H,d,6.5Hz),2.50(3H,s),2.60(1H,dd, 13.8Hz,9.6Hz),2.97(1H,dd,13.8Hz,4.9Hz),4.93(1H,m),5.78 (2H,br),6.03(2H,dm),6.58(1H,s),6.60(2H,dm),7.09(1H,s), 7.31(2H,dm) | ||
87 | (±)-5-(4-aminophenyl)-7-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 145-148 (using water precipitation) | 75 |
Method A | 1H NMR(DMSO-d 6)δ0.88(2H,m),1.05(2H,m),1.22(3H,d,6.5Hz), 2.22(1H,m),2.61(1H,dd,14.0Hz,10.0Hz),2.99(1H,dd,14.0Hz, 5.0Hz),4.97(1H,m),5.78(2H,br),6.05(2H,dm),6.60(1H,s), 6.63(2H,dm),7.06(1H,s),7.36(2H,dm) | ||
88 | (±)-5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 135-138 | 67 |
Method | 1H NMR(CDCl 3)δ1.35(3H,t),1.36(3H,d,6.5Hz),2.79(1H,dd,14.0 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
A | Hz,10.0Hz),2.98(2H,q),2.99(1H,dd,14.0Hz,5.0Hz),3.98(2H, br),5.25(1H,m),6.02(2H,dm),6.63(1H,s),6.73(2H,dm),6.82 (1H,s),7.51(2H,dm,) | ||
89 | (R)-5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 142-144 (using water precipitation) | 47 -602° (c=0.5,EtOH) |
Method E | MS:EI(70eV):[M] +.:407,m/z:392,279,278,253,252 CI:[M+H] +:408,[M] +.:407 | ||
90 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-Trifluoromethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 216-218 | 33 |
Method A | 1H NMR(CDCl 3)δ1.39(3H,d,6.5Hz),2.80(1H,dd,14.0Hz,10.0Hz), 2.93(1H,dd,14.0Hz,5.0Hz),4.06(2H,br),5.28(1H,dm),6.00 (2H,dm),6.61(1H,s),6.69(2H,dm),6.81(1H,s),7.48(2H,dm,) MS:EI(70eV):[M] +.:447,m/z:432,279,253,252 CI:[M+H] +:448,[M] +.:447,m/z:252 | ||
91 | (±)-5-(4-aminophenyl)-7-(5-phenyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 228-230 (50%EtOH-H 2O) | 84 |
Method A | 1H NMR(DMSO-d 6)δ1.28(3H,d,6.5Hz),2.67(1H,dd,14.0Hz,10.0 Hz),3.01(1H,dd,14.0Hz,5.0Hz),5.02(1H,m),5.81(2H,br),6.07 (2H,dm),6.59(1H,s),6.61(2H,dm),7.08(1H,s),7.40(2H,dm), 7.45(3H,m),7.81(2H,d) MS:EI(70eV):[M] +.:455,m/z:440,295,279,253,252 CI:[M+H] +:456,[M] +.:455,m/z:295 | ||
92 | (±)-5-(4-aminophenyl)-7-(5-cyclopropyl amino-methyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 135-138 | 35 |
Method A | 1H NMR(CDCl 3)δ0.45(4H,m),1.33(3H,d,6.5Hz),2.28(1H,m),2.75 (1H,dd,14.0Hz,9.9Hz),2.85(1H,dd,14.0Hz,4.9Hz),4.0(2H, br),4.10(2H,s),5.26(1H,m),6.00(2H,m),6.60(1H,s),6.68(2H, dm),6.80(1H,s),7.49(2H,dm) | ||
93 | (±)-1-(4-aminophenyl)-8-chloro-4-methyl-3-(1,3,4-thiadiazoles-2-yl)-4,5-dihydro-3H-[2,3] benzodiazepine | 125-128 | 79 |
Method A | 1H NMR(DMSO-d 6)δ1.18(3H,d,6.5Hz),2.69(1H,dd,14.0Hz,10.8 Hz),3.14(1H,dd,14.0Hz,5.1Hz),5.05(1H,m),5.83(2H,s),6.62 (2H,dm),7.10(1H,s),7.33(2H,dm),7.51(2H,m) |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
94 | (±)-1-(4-aminophenyl)-8-chloro-4-methyl-3-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-4,5-dihydro-3H-[2,3] benzodiazepine | 131-133 | 88 |
Method A | 1H NMR(DMSO-d 6)δ1.18(3H,d,6.5Hz),2.70(1H,dd,14.0Hz,10.3 Hz),3.11(1H,dd,14.0Hz,5.3Hz),2.50(3H,s),4.96(1H,m),5.80 (2H,s),6.62(2H,dm),7.10(1H,s),7.32(2H,dm),7.51(2H,m) | ||
95 | (±)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 140-144 | 72 |
Method B | MS:EI(70eV):[M] +.:407,m/z:392,293,266 CI:[M+H] +:408,[M] +.:407,m/z:266 | ||
96 | (±)-5-(3-amino-4-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 125 | 70 |
Method B | 1H NMR(500MHz)(DMSO-d 6)δ1.17(3H,d,6.5Hz),2.10(3H,s),2.51 (3H,s),2.72(1H,dd,14.1Hz,9.1Hz),3.05(1H,dd,14.1Hz,4.5 Hz),5.01(2H,s),5.03(1H,m),6.07(2H,dm),6.55(1H,s),6.70 (1H,dd),6.83(1H,d,1.2Hz),7.00(1H,d,7.8Hz),7.06(1H,s) | ||
97 | (±)-5-(3-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 197-198 (iPrOH) | 77 |
Method B.C | 1H NMR(500MHz)(DMSO-d 6)δ1.17(3H,d,6.5Hz),2.51(3H,s),2.77 (1H,dd,14.2Hz,8.6Hz),3.08(1H,dd,14.2Hz,4.3Hz),5.06(1H, m),5.24(2H,s),6.07(2H,dm),6.54(1H,s),6.67(1H,d),6.71(1H, d),6.74(1H,d),7.06(1H,s) | ||
98 | (±)-1-(4-aminophenyl)-4-methyl-3-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8-methoxyl group-4,5-dihydro-3H-[2,3] benzodiazepine | 180-184 | 84 |
Method D | MS:EI(70eV):[M] +.:379,m/z:364,265,238,223 CI:[M+H] +:380,[M] +.:379,m/z:223 | ||
99 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-methyl-6H-1,3,4-thiadiazine-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 154-157 | 85 |
Method A | 1H NMR(DMSO-d 6)δ1.20(3H,d,6.5Hz),2.10(3H,s),2.55(1H,dd, 14.0Hz,11Hz),2.92(1H,dm),2.92(1H,dd,14.5Hz),3.28(1H,d, 14.5Hz),5.10(1H,m),5.70(2H,s),6.02(2H,dm),6.55(2H,dm), 7.01(1H,s),7.38(2H,dm),7.60(1H,s) | ||
100 | (±)-5-(4-aminophenyl)-7-(5,6-dihydro-5- | 172-176 | 83 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Oxo-4H-1,3,4-thiadiazine-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | |||
Method A | 1H NMR(DMSO-d 6)δ1.16(3H,d,6.5Hz),2.49(1H,dd,14.0Hz,10.0 Hz),2.87(1H,dd,14.0Hz,5.2Hz),3.31(2H,s),4.78(1H,m),5.68 (2H,s),6.05(2H,dm),6.65(1H,s),6.66(2H,dm),7.00(1H,s), 7.32(2H,dm),10.5(1H,s) | ||
101 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-oxo-4,5-dihydro-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | 263-264 | 47 |
Method C | 1H NMR(DMSO-d 6)δ1.17(3H,d,6.5Hz),2.58(1H,dd,14.0Hz,10.4 Hz),2.97(1H,dd,14.0Hz,5.4Hz),4.71(1H,m),5.65(2H,s),6.04 (2H,dm),6.61(2H,dm),6.62(1H,s),7.01(1H,s),7.23(2H,dm), 11.81(1H,br s) MS:EI(70eV):[M] +.:395,m/z:394,306,252 CI:[M+H] +:396,[M] +.:395,m/z:280 | ||
102 | (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 145-149 | 86 -663° (c=0.5,EtOH) |
Method A | MS:EI(70eV):[M] +.:377,m/z:252 CI:[M+H] +:378,[M] +.:377,m/z:252 | ||
103 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-methyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-5-yl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | 213 (EtOH) | 67 |
Method A | 1H NMR(DMSO-d 6)δ1.23(3H,d,6.5Hz),2.70(1H,dd,13.8Hz,10.2 Hz),3.03(1H,dd,13.8Hz,4.2Hz),3.06(3H,s),4.91(1H,m),5.90 (2H,s),6.08(2H,dm),6.61(1H,s),6.61(2H,dm),7.06(1H,s), 7.30(2H,dm) | ||
104 | (±)-5-(4-aminophenyl)-7-(2-cyclopropyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 265-267 | 82 |
Method A | 1H NMR(DMSO-d 6)δ0.85(4H,m),1.22(3H,d,6.5Hz),2.75(1H,dd, 14.0Hz,10.0Hz),2.75(1H,m),3.02(1H,dd,14.0Hz,4.7Hz),4.92 (1H,m),5.90(2H,s),6.07(2H,dm),6.60(1H,s),6.63(2H,dm), 7.04(1H,s),7.30(2H,dm) | ||
105 | (±)-5-(4-aminophenyl)-7-(2-ethyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-2-yl)-8- | 212-214 | 59 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also | |||
Method A | 1H NMR(CDCl 3)δ1.25(3H,t),1.27(3H,d,6.5Hz),2.80(1H,dd,14.0 Hz,9.0Hz),3.01(1H,dd,14.0Hz,4.0Hz),3.72(2H,q),4.07(2H, br),5.13(1H,m),6.03(2H,dm),6.65(1H,s),6.67(2H,dm),6.80 (1H,s),7.37(2H,dm) MS:EI(70eV):[M] +.:423,m/z:408,279,252,160 CI:[M+H] +:424,[M] +.:423 | ||
106 | (±)-5-(4-aminophenyl)-7-(4-carboxyl-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | >260 (dec.) | 97 |
Method A | MS:EI(70eV):[M] +.:422,m/z:407,279,253 | ||
107 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-tetrazyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | >360 | 68 |
Method A | MS:EI(70eV):[M] +.:363,m/z:295,294,252 CI:[M+H] +:364,[M] +.:363,m/z:295 | ||
108 | (±)-5-(4-aminophenyl)-8-methyl-7-(1,2,4-oxadiazole-3-yl)-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine hydrochloride | 124-126 | 48 |
Method A | MS:EI(70eV):[M] +.:363,m/z:348,253,252 CI:[M+H] +:364,[M] +.:363,m/z:252 | ||
109 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 2,4-oxadiazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 130-135 | 74 |
Method A | MS:EI (70eV) (hydrochloride): [M] +.:377,m/z:362,278,252 CI:[M+H] +:378,[M] +.:377,m/z:252 | ||
110 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-methyl-thiazole-4-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 132-135 | 22 |
Method C | MS:EI(70eV):[M] +.:392,m/z:377,279,253,252 CI:[M+H] +:393,[M] +.:392 | ||
111 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-pyrimidyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 233-235 (EtOH) | 96 |
Method A | 1H NMR(DMSO-d 6)δ1.23(3H,d,6.5Hz),2.50(1H,dd,14.0)Hz,10.0 Hz),2.89(14.0Hz,4.8Hz),5.18(1H,m),5.71(2H,s),6.03(2H, |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
dm),6.58(2H,dm),6.60(1H,s),6.60(1H,t,4.8Hz),7.43(1H,s), 7.30(2H,dm),8.33(2H,d,4.8Hz) | |||
112 | (±)-5-(4-aminophenyl)-7-(3-chlorine pyridazine-6-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 164-166 (EtOH) | 94 |
Method A | MS:EI(70eV):[M] +.:407/409,m/z:392/394,355,279,278,253,252 CI:[M+H] +:408/410,[M] +.:407/409,m/z:279 | ||
113 | (±)-5-(4-aminophenyl)-8-methyl-7-(1H (2H)-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 178-181 | 64 |
Method A | MS:EI(70eV):[M] +.:362,m/z:347,279,252 | ||
114 | (±)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid H (2H)-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 166-169 | 72 |
Method A | MS:EI(70eV):[M] +.:376,m/z:361,279,252 | ||
115 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-methyl-2H-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 182-183 | 83 |
Method A | MS:EI(70eV):[M] +.:376,m/z:361,279,252 | ||
116 | (±)-5-(4-aminophenyl)-8-methyl-7-(1-methyl isophthalic acid H-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 165-168 | 83 |
Method A | MS:EI(70eV):[M] +.:376,m/z:361,253,252 | ||
117 | (±)-5-(4-aminophenyl)-8-methyl-7-(2,5-dimethyl-2H-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | 185-187 | 78 |
Method A | MS:EI(70eV):[M] +.:390,m/z:375,279,265,252 | ||
118 | (±)-5-(4-aminophenyl)-8-methyl-7-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | 197-200 | 85 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Method C | MS:EI(70eV):[M] +.:390,m/z:375,253,252 | ||
119 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 158-160 | 83 -515° (c=0.38,CHCl 3) |
Method B | 1H NMR(DMSO-d 6)δ1.18(3H,d,5.4Hz),2.07(s,3H),2.47(s,3H), 2.57(dd,1H,13.7Hz,10.3Hz),2.95(dd,1H,13.7Hz,4.9Hz),4.92 (m,1H),5.2-5.8(br,2H),6.01(s,br,1H),6.06(s,br,1H),6.55 (s,1H),6.64(d,1H,8.2Hz),7.04(s,1H),7.17(d,1H,8.2Hz),7.25 (s,br,1H) MS:EI(70eV):[M] +.:407,m/z:392,293,278,266 CI:[M+H] +:408,[M] +.:407 |
Embodiment 120-131
Synthetic 2 of the acetylamino-phenyl group, the general operation of 3-benzodiazepine of containing
To contain 2 of aminophenyl group, 3-benzodiazepine is dissolved in the methylene dichloride, stirs with excessive acetic anhydride via in room temperature.After finishing reaction, dry then with sodium hydrogen carbonate solution and water washing mixture, and concentrate.
Table 11.
By the acetylamino phenyl group replace 2,3-benzodiazepine derivative
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
120 | (±)-5-(4-acetylamino phenyl)-8-methyl-7-(5-methyl-thiazol-2-yl)-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 176-179 | 65 |
121 | (±)-5-(4-acetylamino phenyl)-8-methyl-7-(4-methyl-thiazol-2-yl)-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 236-238 (50% EtOH-H 2O ) | 65 |
122 | (±)-5-(4-acetylamino phenyl)-7-(4; 5-dihydro-thiazol-2-yl)-8-methyl-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 211-213 (EtOH) | 96 |
123 | (R)-5-(4-acetylamino phenyl)-8-methyl | 126 is (heavy | 95 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also | Row) 172-174 (EtOH) | -140° (c=0.44, CHCl 3) | |
124 | (S)-5-(4-acetylamino phenyl)-8-methyl-7-(2-thiazolyl)-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 124-128 | 95 +134° (c=0.48, CHCl 3) |
125 | (R)-5-(4-acetylamino phenyl)-7-(4; 5-dihydro-thiazol-2-yl)-8-methyl-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 143-145 | 95 +108° (c=0.45, CHCl 3) |
126 | (S)-5-(4-acetylamino phenyl)-7-(4; 5-dihydro-thiazol-2-yl)-8-methyl-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 148-154 | 91 -111° (c=048, CHCl 3) |
127 | (±)-5-(4-acetylamino phenyl)-7-(4; 5-dihydro-oxazoles-2-yl)-8-methyl-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 124-128 | 44 |
128 | (±)-5-(4-acetylamino phenyl)-8-methyl-7-(2-pyrimidyl)-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 162-163 (EtOH) | 96 |
129 | (±)-5-(4-acetylamino phenyl)-7-(3-chloro-pyridazine-6-yl)-8-methyl-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 164-170 | 78 |
130 | (R)-5-(4-acetylamino phenyl)-8-methyl-7-(5-methyl isophthalic acid; 3; 4-thiadiazoles-2-yl)-8; 9-dihydro-7H-1; the 3-dioxole also-[4; 5-h] [2,3] benzodiazepine | 276-277 (MeOH) | 73 -114° (c=0.5, CHCl 3) |
131 | (±)-5-(4-acetylamino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid; 3; 4-thiadiazoles-2-yl)-8; 9-dihydro-7H-1; 3-dioxole also [4; 5-h] [2,3] benzodiazepine | 258-262 | 63 |
Embodiment 132
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-7-(4,5-dihydro-thiazole-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-7-thiocarbamyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to about the described method of initial compounds I, prepared this compound from initial compounds XXXI.Fusing point: 123-125 ℃.Productive rate: 70%.
Step B
According to embodiment 9 described methods, the product of steps A is changed into title compound.Fusing point: 130-135 ℃.Productive rate: 81%.
Embodiment 133
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-7-(thiazol-2-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, obtained title compound from the described intermediate of the steps A of embodiment 132.Fusing point: 138-142 ℃.Productive rate: 55%.
Embodiment 134
(R)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl-4-nitro Phenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate also
According to about the described method of initial compounds XI, prepared this compound from initial compounds XXXI.Fusing point: 193-196 ℃.Productive rate: 85%.[α]
D:-500.0 ° of (c=0.5; CHCl
3).
Step B
Compound and 1.28g (21.3mmol) propionyl hydrazine that 2.50g (6.0mmol) is obtained in steps A reacted 2 hours at 70 ℃ in the 10ml dimethyl formamide.The refrigerative reaction mixture is poured in the water, filtered and collect the precipitation that obtains.In 24ml ethanol, this wet material was further reacted 1 hour at boiling point with the 0.5ml concentrated hydrochloric acid.Evaporating solvent is dissolved into resistates in the methylene dichloride, and extracts with sodium hydrogen carbonate solution and water.Evaporating solvent generates thick title product, carries out purifying by column chromatography, and the mixture that uses normal hexane-ethyl acetate (1: 1) obtains 1.15g (productive rate: product 49%) as eluent.Fusing point: 129-130 ℃.
Embodiment 135
(R)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(5-propyl group-1,3,4-thiadiazoles -2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
According to embodiment 134 described methods, but be to use daminozide, obtained title compound.Fusing point: 143-145 ℃.Productive rate: 73%.[α]
D:+343.3 ° of (c=0.5; CHCl
3).
Embodiment 136
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-7-(1,3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 8-methyl-5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfonyl hydrazine also
According to about the described method of raw material XVIII, the steps A intermediate of embodiment 134 is changed into carbon sulfonyl hydrazine.Fusing point: 109-115 ℃.Productive rate: 91%.[α]
D:-276.5 ° of (c=0.5; CHCl
3).
Step B
Be similar to embodiment 25 described methods, make the compound of steps A and the hydrochloric acid reaction of triethyl orthoformate and catalytic amount, generate title product.Fusing point: 182-189 ℃.Productive rate: 92%.[α]
D:+356.0 ° of (c=0.5; CHCl
3).
Embodiment 137
(R)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(5-methoxymethyl-1,3,4- Thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzene And diaza
Make embodiment 136 the steps A compound (2.07g, 5.0mmol) in the 10ml dimethyl formamide with 1.86g (5.5mmol) pentachlorophenol methoxyacetic acid ester 50 ℃ the reaction 2 hours.The precipitation that dilute with water reaction mixture, filtering separation obtain.The intermediate that should wet is absorbed in the ethanol (24ml), adds the 0.50ml concentrated hydrochloric acid, makes its boiling 1 hour.Evaporating solvent generates resistates, it is dissolved in the methylene dichloride, and with 5% sodium carbonate solution and water washing solution.Evaporating solvent generates thick title product, carries out purifying by column chromatography; The mixture of normal hexane-ethyl acetate (2: 1) is used as eluent, generates the 2.21g pure products.Fusing point: 153-155 ℃.Productive rate: 91%.[α]
D:+317.5 ° of (c=0.5; CHCl
3).
Use suitable activatory carboxylic acid derivative as reagent (for example: the chloride of acid of corresponding carboxylic acid, acid anhydrides, pentachlorobenzene phenolic ester, N-hydroxy-succinamide ester), be similar to embodiment 137 described methods, prepared the compound of embodiment 138-148.
Embodiment 138
(R)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(5-sec.-propyl-1,3,4-thiophene two Azoles-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo two Azatropylidene
Fusing point: 130-133 ℃.Productive rate: 90%.
Embodiment 139
(R)-7-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl-4-nitre The base phenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine Assorted
Fusing point: 126-130 ℃.Productive rate: 93%.
Embodiment 140
(R)-7-(5-hydroxymethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl-4- Nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo two Azatropylidene
Fusing point: 142-145 ℃.Productive rate: 67%.
Embodiment 141
(R)-7-(5-acetoxy-methyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-first Base-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] Benzodiazepine
Fusing point: 110-115 ℃.Productive rate: 97%.
Embodiment 142
(R)-7-(5-cyano methyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl-4- Nitrophenyl)-8,9-dihydro-7H-1, the 3-dioxole is also[4,5-h] [2,3]
Benzo two Azatropylidene
Fusing point: 118-122 ℃.Productive rate: 98%.
Embodiment 143
(R)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-(5-methylthiomethyl-1,3,4- Thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzene And diaza
Fusing point: 132-134 ℃.Productive rate: 96%.
Embodiment 144
(R)-7-(5-ethoxy carbonyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl -4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzene And diaza
Fusing point: 115-118 ℃.Productive rate: 80%.[α]
D:+140.3 ° of (c=0.5; CHCl
3).
Embodiment 145
(R)-7-(5-benzyloxycarbonyl-aminomethyl-1,2,3,4-thiadiazoles-2-yl)-8-methyl -5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 240-243 ℃.Productive rate: 95%.
Embodiment 146
(R)-8-methyl-5-(3-methyl-4-nitrophenyl)-7-{5-[1-(1E)-propylene-1- Base]-1,3,4-thiadiazoles-2-yl }-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Fusing point: 232-237 ℃.Productive rate: 28%.[α]
D:-359.2 ° of (c=0.4; CHCl
3).
Embodiment 147
(R)-7-(5-hexyl-1,3,4-thiadiazoles-2-yl)-8-methyl-5-(3-methyl-4-nitro Phenyl)-8,9-dihydro-7H-1, the 3-dioxole is also[4,5-h] [2,3]
Benzodiazepine
Fusing point: 217-224 ℃.Productive rate: 66%.
Embodiment 148
(R)-7-(5,6-dihydro-5-oxo-4H-1,3,4-thiadiazine-2-yl)-8-methyl -5-(3-methyl-4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Use embodiment 43 described methods, but with the pentachlorophenol chloracetate as alkylating agent, from the compound that the steps A of embodiment 136, obtains title compound.Fusing point: 207-211 ℃.Productive rate: 70%.[α]
D:+378.5 ° of (c=0.5; CHCl
3).
Embodiment 149
(R)-and 8-methyl-5-(4-nitrophenyl)-7-(1,3,4-oxadiazole-2-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 45 described methods, obtained title compound from (R)-N '-{ 8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl also }-formyl hydrazine.Fusing point: 145-147 ℃.Productive rate: 35%, [α]
D:-604.0 ° of (c=0.5; CHCl
3).
Embodiment 150
(±)-8-methyl-5-(4-nitrophenyl)-7-(1,2,3,4-thiatriazole-5-yl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
1.00g (2.5mmol) raw material XVIII, the solution of 0.37ml (4.6mmol) trifluoroacetic acid in the 10ml methane amide were stirred 5 minutes at 25 ℃.Dropwise add the solution of 0.16g (2.5mmol) Sodium Nitrite in 0.30ml water then.0.5 after hour, the dilute with water reaction mixture leaches the precipitation of formation, washes with water and dry, generates 0.92g (90%) title compound.Fusing point: 109-110 ℃.
Embodiment 151
(±)-8-methyl-5-(4-nitrophenyl)-7-(2-methyl isophthalic acid, 3-oxazole-5-yl)-8,9- Dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(±)-N '-2-[8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-yl also]-the 2-oxoethyl }-ethanamide
With 1.5g (4.6mmol) (±)-8-methyl-5-(4-nitrophenyl)-8; 9-dihydro-7H-1; 3-dioxole also [4; 5-h] [2; 3] benzodiazepine , 0.5g (4.6mmol) N-acetyl-glycine and 1.0g (5.0mmol) 1, the solution of 3-dicyclohexyl carbodiimide stirred 3 hours at 25 ℃ in the 15ml methylene dichloride.Leach sedimentary 1, the 3-dicyclohexylurea (DCU), evaporated filtrate is to doing.The mixture that uses ethyl acetate-hexane (1: 1) by column chromatography purifying crude product, generates 1.1g (58%) title compound as eluent.
Step B
0.74g (2.8mmol) triphenylphosphine dissolved in the 10ml methylene dichloride, is added the solution of 0.2ml (2.8mmol) bromine in the 1ml methylene dichloride.After 30 minutes, add compound and the solution of 1.0ml (7.1mmol) triethylamine in the 5ml methylene dichloride that 1.0g (2.4mmol) prepares in steps A, boiling mixture is 3 hours under nitrogen.Wash the solution that obtains with water, drying, and be concentrated into dried.The mixture that uses ethyl acetate-hexane (1: 1) by column chromatography purifying crude product, generates 0.6g (62%) title compound as eluent.Fusing point: 203-205 ℃.
Embodiment 152
(±)-7-(2,4-dimethyl-1,3-oxazole-5-yl)-8-methyl-5-(4-oil of mirbane Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 151 described methods, but be to use (±)-N-(2-[8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine -7-yl]-1-methyl-2-oxoethyl }-ethanamide is as intermediate, obtained title compound.Fusing point: 76-78 ℃; Productive rate: 68%.
Embodiment 153
(R)-5-(3-chloro-4-nitrophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 7-(tert-butoxycarbonyl)-5-(3-chloro-4-nitrophenyl)-8-methyl-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also
According to document (Anderson etc., Am.Chem.Soc.
117: 12358 (1995)) described synthetic method, use 3-chloro-4-nitrobenzaldehyde and tert-butyl carbazate as key reagents, prepared this compound.Fusing point: 160-162 ℃.
Step B
(R)-and 5-(3-chloro-4-nitrophenyl)-8-methyl base-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
Compound (the 8.2g that will in steps A, obtain; 18.2mmol) be dissolved in the ethyl acetate (82ml) that contains 12% hydrochloric acid.Solution was kept 3 hours in room temperature.Evaporating solvent is dissolved into resistates in the ethyl acetate then, and with saturated sodium hydrogen carbonate solution and water washing.Evaporation generates 5.3g (81%) title product.Fusing point: 165-170 ℃.[α]
D:+65.0°(c=0.5;CHCl
3).
Step C
(R)-and 5-(3-chloro-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate also
According to about the described method of raw material XI, the intermediate preparation that obtains from step B this compound.Fusing point: 132-134 ℃.Productive rate: 88%.[α]
D:-533.0 ° of (c=0.5; CHCl
3).
Step D
According to the described method of the method B of embodiment 28, the compound for preparing from step C has obtained title compound.Fusing point: 151-152 ℃.Productive rate: 89%.[α]
D:+284.1 ° of (c=0.5; CHCl
3).
Embodiment 154
(R)-5-(3-chloro-4-nitrophenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiophene Diazole-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo Diaza
Steps A
(R)-and 5-(3-chloro-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfonyl hydrazine also
According to about the described method of raw material XVIII, the compound that will obtain in the step C of embodiment 153 changes into title compound.Fusing point: 126-127 ℃; Productive rate: 85%.
Step B
According to embodiment 137 described methods, use the compound that in steps A, obtains to prepare title compound.Fusing point: 208-210 ℃; Productive rate: 65%.[α]
D:+470.6 ° of (c=0.5; CHCl
3).
Embodiment 155
(±)-8-methyl-7-(3-methyl-isoxazole-5-bases)-5-(4-nitrophenyl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(±)-1-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-yl also }-butane-1, the 3-diketone
With 4.0g (12.3mmol) (±)-8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine , the solution of 0.52ml (13.5mmol) diketene in 80ml toluene stirred 3 hours at 80 ℃.Wash reaction mixture with water, drying, and concentrate.Resistates is ground with Di Iso Propyl Ether, generate 4.0g (80%) title compound.Fusing point: 169-171 ℃.
Step B
(±)-4-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-yl also }-4-sulfo--butane-2-ketone
Compound, the solution of 2.4g (5mmol) LawessonShi reagent in 500ml toluene of 3.0g (7.2mmol) steps A were stirred 4 hours at reflux temperature.Filter reaction mixture, and evaporating solvent then.The mixture that uses ethyl acetate-hexane (1: 3) by column chromatography purifying crude product, generates 2.1g (70%) title compound as eluent.Fusing point: 178-185 ℃.
Step C
The compound that 1.9g (4.5mmol) is obtained in step B and the solution of 0.6g (9.0mmol) oxammonium hydrochloride stir reflux 3 hours in 20ml ethanol.The dilute with water reaction mixture, and leach the precipitation of formation.The mixture that uses ethyl acetate-hexane (1: 3) by column chromatography purifying crude product, generates 0.60g (32%) title compound as eluent.Fusing point: 179-182 ℃.
Embodiment 156
(R)-5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiophene Diazole-2-yl)-and 7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 7-(tert-butoxycarbonyl)-5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to document (Anderson etc., J.Am.Chem Soc.
117: 12358 (1995)) described synthetic method, but be to use 3,5-dimethyl-4-nitrobenzaldehyde and tert-butyl carbazate have prepared this compound as key reagents.Fusing point: 222-223 ℃.[α]
D:-443.0°(c=0.5;CHCl
3).
Step B
(R)-and 5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to the described method of embodiment 153 step B, the compound that obtains in steps A is hydrolyzed.Fusing point: 193 ℃; Productive rate: 88%.[α]
D:+181 ° of (c=0.5; CHCl
3).
Step C
(R)-and 5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate also
According to about the described method of initial compounds XI, will change into title carbon sulfenyl derivative at the compound that step B obtains.Fusing point: 216 ℃; Productive rate: 82%.[α]
D:-389 ° of (c=0.5; CHCl
3).
Step D
According to embodiment 28 described method B, the compound that obtains from step C the title compound of this embodiment.Fusing point: 235 ℃; Productive rate: 86%.[α]
D:+221 ° of (c=0.5; CHCl
3).
Embodiment 157
(R)-5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-Evil Diazole-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo Diaza
According to embodiment 45 described methods, the thiosemicarbazide type intermediate of the step D of usefulness mercuric acetate (II) Processing Example 156 16 hours.Fusing point: 132-133 ℃; Productive rate: 90%.[α]
D:-436 ° of (c=0.5; CHCl
3).
Embodiment 158
(R)-and 5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-7-(2-thiazolyl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 5-(3,5-dimethyl-4-nitrophenyl)-8-methyl-7-thiocarbamyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
By about the described method of raw material I, from the compound that among the step B of embodiment 156, obtains this intermediate, but in reaction process, also noticed the remarkable hydrolysis of title product to the urea derivatives of correspondence.The mixture that uses hexane-ethyl acetate (3: 1) has separated title compound as eluent by column chromatography.Fusing point: 228-230 ℃; Productive rate: 18%.
Step B
As described in embodiment 1, make the midbody compound and the reaction of bromoacetaldehyde diethyl acetal that in steps A, obtain.Fusing point: 167 ℃; Productive rate: 46%.
Embodiment 159
(R)-8-methyl-7-(2-methyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-5- Base)-and 5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-phenyl-(8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -3-carbon sulfenyl also)-carbamate
According to preparing about initial compounds XXVI is described, still, from (R)-8-methyl-5-(4-nitrophenyl)-8, also [4,5-h] [2,3] benzodiazepine preparation of 9-dihydro-7H-1,3-dioxole.Without being further purified the use crude product.
Step B
(R)-1-methyl-3-{8-methyl-5-(4-nitrophenyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl also }-urea
According to about the described method of racemic initial compounds XXVII, make the intermediate and the methylamine reaction of steps A.Fusing point: 164 ℃; Productive rate: 63%..[α]
D:-526 ° of (c=0.5; CHCl
3).
Step C
According to embodiment 46 described methods, make compound and the bromine reaction of step B, generate title product.Fusing point: 177-180 ℃; Productive rate: 98%.[α]
D:+438 ° of (c=0.5; CHCl
3).
Embodiment 160
(±)-7-(5,5-dimethyl-4-oxo-4,5-dihydro-thiazol-2-yl)-8-methyl -5-(4-nitrophenyl)-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
In the suspension of 1.20g (2.86mmol) raw material I in the 10ml dimethyl formamide, add 1.67g (8.58mmol) ethyl-alpha-brominated isobutyrate.Mixture was stirred 1 hour at 80 ℃, and stirred 23 hours at 100-110 ℃.Dilute with water solution extracts isolating oily matter in the methylene dichloride.After washing and the drying, evaporating solvent, the mixture that uses hexane-ethyl acetate (1: 1) be as eluent, by the column chromatography purifying resistates.Evaporation contains the fraction of principal product, generates the gluey title compound of 0.80g.
Embodiment 161
(R)-and 8-methyl-5-(4-nitrophenyl)-7-(1,2,3-thiadiazoles-5-yl)-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
In the ethereal solution that contains highly excessive diazomethane, dropwise add the solution of 2.42g (3.0mmo1) raw material XII in the 40ml tetrahydrofuran (THF) at-15 ℃.Solution was kept 5 days in room temperature, confirm to transform fully up to TLC.Evaporation generates resistates, and the mixture that uses hexane-ethyl acetate (3: 1) carries out purifying as eluent by column chromatography.Obtain the 2.13g title product.Fusing point: 175-176 ℃.[α]
D:-96°(c=0.5;CHCl
3).
Embodiment 162
(R)-5-(2-bromo-3-methyl-4-nitrophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiophene Diazole-2-yl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzo Diaza
Steps A
(R)-and 5-(2-bromo-3-methyl-4-nitrophenyl)-7-(tert-butoxycarbonyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to document (Anderson etc., J.Am.Chem.Soc.
117: 12358 (1995)) disclosed method, use 2-bromo-3-tolyl aldehyde and tert-butyl carbazate to prepare this compound.
MS:EI(70eV):[M]
+.:517/519,mz:417/419,376/378,57
CI:[M+H]
+:518/520
Step B
(R)-and 5-(2-bromo-3-methyl-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to embodiment 153 step B disclosed methods, hydrolysis the compound that in steps A, obtains.
MS:EI(70eV):[M]
+.:417/419,m/z:402/404,374/376,338,160
CI:[M+H]
+:418/420,[M]
+.:417/419
Step C
(R)-and 5-(2-bromo-3-methyl-4-nitrophenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate also
According to about the described method of raw material XI, the compound that will obtain in step B changes into title compound.
MS:EI(70eV):[M]
+.:495/497,m/z:460/462,401/403,355/357
CI:[M+H]
+:496/498/500,m/z:460/462
Step D
According to the described method of the method B of embodiment 28, the title compound that obtains in step C is further reacted with acethydrazide, generate foamed title compound.
MS:EI(70eV):[M]
+.:515/517,m/z:500/502,401/403,59
CI:[M+H]
+:516/518
Table 12.
Contain 2 of aminophenyl group, 3-benzodiazepine
(except as otherwise noted, at the 500MHz record
1H NMR spectrum)
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
163 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(4,5-dihydro-thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 125-128 | 53 -282.0° (c=0.5, CHCl 3) |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Method * B | 1H NMR(DMSO-d 6)d 1.10(3H,d,6.0Hz),2.06(3H,s),2.53 (1H,dd,14.0Hz,10.0Hz),2.86(1H,dd,14.0Hz,4.5Hz), 3.0-3.2(2H,m),3.93(1H,m),4.05(1H,m),4.85(1H,m), 5.35(2H,s),6.04(1H,s),6.07(1H,s),6.55(1H,s),6.61 (1H,d,8.5Hz),6.98(1H,s),7.13(1H,d,br,8.5Hz),7.22 (1H,s,br) | ||
164 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 124-127 | 86 -619.5° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.16(3H,d,6.0Hz),2.09(3H,s),2.59 (1H,dd,14.0Hz,10.5Hz),2.95(1H,dd,14.0Hz,5.5Hz), 5.01(1H,m),5.47(2H,s,br),6.03(1H,d,1.1Hz),6.08 (1H,d,1.1Hz),6.58(1H,s),6.64(1H,d,8.0Hz),6.83(1H, d,3.5Hz),7.05(1H,s),7.21(1H,dd,8.0Hz,2.0Hz),7.28 (1H,d,3.5Hz),7.31(1H,d,2.0Hz) | ||
165 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 129-133 (EtOH) | 90 -534.9° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.20(3H,d,6.1Hz),1.23(3H,t,7.6Hz), 2.07(3H,s),2.58(1H,dd,14.0Hz,10.6Hz),2.85(2H,q, 7.6Hz),2.95(1H,dd,14.0Hz,5.4Hz),4.93(1H,m),5.50 (2H,s,br),6.03(1H,d,1.0Hz),6.08(1H,d,1.0Hz),6.57 (1H,s),6.63(1H,d,8.4Hz),7.06(1H,s),7.20(1H,dd, 8.4Hz,2.1Hz),7.25(1H,d,2.1Hz) MS:EI(70eV):[M] +.:421,m/z:406,293,266 CI:[M+H] +:422,[M] +.:421 | ||
166 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-propyl group-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 150-154 (EtOH) | 56 -516.0° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-D 6)d 0.91(t,7.5Hz),1.20(3H,d,6.1Hz), 1.66(2H,m),2.08(3H,s),2.58(1H,dd,13.8Hz,10.6Hz), 2.80(2H,t,7.2Hz),2.96(1H,dd,13.8Hz,5.1Hz),4.94 (1H,m),5.50(2H,s),6.03(1H,s),6.08(1H,s),6.57(1H, s),6.64(1H,d,8.3Hz),7.05(1H,s),7.19(1H,dd,8.3 Hz,2.1Hz),7.25(1H,d,2.1Hz) | ||
167 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl | 143-148 | 63 |
* referring to front embodiment 60-118 provide about the reduction each 2, the general operation of the nitro of 3-benzodiazepine
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | (EtOAc) | -527.3° (c=0.5, CHCl 3) | |
Method B | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.1Hz),2.08(3H,s),2.61 (1H,dd,13.6Hz,10.6Hz),3.00(1H,dd,13.6Hz,5.0Hz), 5.00(1H,m),5.52(2H,s,br),6.03(1H,d,0.7Hz),6.08 (1H,d,0.7Hz),6.58(1H,s),6.64(1H,d,8.3Hz),7.07 (1H,s),7.20(1H,dd,8.3Hz,2.1Hz),7.28(1H,d,2.1 Hz),8.78(1H,s) MS:EI(70eV):[M] +.:393,m/z:378,266 CI:[M+H] +:394,[M] +.:393 | ||
168 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 171-172 (EtOH) | 86 -540.0° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.1Hz),2.08(3H,s),2.60 (1H,dd,14.0Hz,11.0Hz),2.97(1H,dd,14.0Hz,5.4Hz), 4.57(1H,d,12.7Hz),4.60(1H,d,12.7Hz),4.98(1H,m), 5.3-5.8(2H),6.03(1H,s),6.08(1H,s),6.58(1H,s), 6.65(1H,d,8.6Hz),7.06(1H,s),7.21(1H,dd,8.6Hz, 2.2Hz),7.26(1H,d,2.2Hz) | ||
169 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-sec.-propyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 134-140 | 83 -518.8° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.20(3H,d,6.2Hz),1.26(3H,d,6.9Hz), 1.28(3H,d,6.9Hz),2.07(3H,s),2.58(1H,dd,13.8Hz, 10.8Hz),2.95(1H,dd,13.8Hz,5.5Hz),3.18(1H,m),4.94 (1H,m),5.51(2H,s,br),6.03(1H,s),6.08(1H,s),6.57 (1H,s),6.64(1H,d,8.4Hz),7.06(1H,s),7.21(1H,dd, 8.4Hz,2.1Hz),7.24(1H,d,2.1Hz) | ||
170 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-cyclopropyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 124-128 | 47 -504.1° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-D 6)d 0.86(2H,m),1.03(2H,m),1.16(3H,d, 6.2Hz),2.07(3H,s),2.23(1H,m),2.57(1H,dd,14.0Hz, 10.8Hz),2.95(1H,dd,14.0Hz,5.5Hz),4.92(1H,m),5.50 (2H,s),6.03(1H,s),6.08(1H,s),6.55(1H,s),6.64(1H, d,8.3Hz),7.05(1H,s),7.19(1H,dd,8.3Hz,2.1Hz), 7.23(1H,d,2.1Hz) |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
171 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-hydroxymethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 184-186 | 75 -540.0° (c=0.5, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.20(3H,d,6.1Hz),2.08(3H,s),2.60 (1H,dd,13.9Hz,10.6Hz),2.97(1H,dd,13.9Hz,5.3Hz), 4.61(2H,d,5.8Hz),4.95(1H,m),5.52(2H,s),5.81(1H, t,5.8Hz),6.03(1H,s),6.08(1H,s),6.58(1H,s),6.65 (1H,d,8.5Hz),7.06(1H,s),7.19(1H,dd,8.5Hz,2.0Hz), 7.26(1H,d,2.0Hz) | ||
172 | (R)-7-(5-acetoxy-methyl-1,3,4-thiadiazoles-2-yl)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 204-206 (EtOH) | 45 -560.0° (c=0.5, CHCl 3) |
Method E | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.2Hz),2.07(3H,s),2.08 (3H,s),2.60(1H,dd,14.0Hz,11.0Hz),2.97(1H,dd,14.0 Hz,5.4Hz),4.99(1H,m),5.20(1H,d,13.1Hz),5.24(1H, d,13.1Hz),5.55(2H,s),6.03(1H,s),6.09(1H,s),6.59 (1H,s),6.65(1H,d,8.4Hz),7.06(1H,s),7.21(1H,dd, 8.4Hz,2.1Hz),7.26(1H,d,2.1Hz) | ||
173 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-cyano methyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 135-140 | 25 -517.9° (c=0.5, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.2Hz),2.08(3H,s),2.61 (1H,dd,13.9Hz,11.0Hz),2.99(1H,dd,13.9Hz,5.5Hz), 4.40(2H,s),4.96(1H,m),5.55(2H,s),6.03(1H,d,0.7 Hz),6.09(1H,d,0.7Hz),6.59(1H,s),6.65(1H,d,8.3Hz), 7.06(1H,s),7.21(1H,dd,8.3Hz,1.8Hz),7.26(1H,d, 1.8Hz) | ||
174 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methylthiomethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 177-180 (EtOH) | 57 -496.0° (c=0.5, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.1Hz),2.03(3H,s),2.08 (3H,s),2.60(1H,dd,13.8Hz,10.6Hz),2.97(1H,dd,13.8 Hz,5.3Hz),3.91(1H,d,14.7Hz),3.95(1H,d,14.7Hz), 4.96(1H,m),5.52(2H,s),6.03(1H,d,0.9Hz),6.09(1H, d,0.9Hz),6.59(1H,s),6.65(1H,d,8.4Hz),7.06(1H,s), 7.21(1H,dd,8.4Hz,2.0Hz),7.25(1H,d,2.0Hz) | ||
175 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-second | 135-140 | 86 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Oxygen base carbonyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | -606.3° (c=0.5, CHCl 3) | ||
Method E | 1H NMR(DMSO-d 6)d 1.15(3H,d,6.2Hz),1.30(3H,t,7.1Hz), 2.09(3H,s),2.64(1H,dd,13.8Hz,11.3Hz),2.99(1H,dd, 13.8Hz,5.4Hz),4.30(2H,m),5.11(1H,m),5.65(2H,s), 6.04(1H,s),6.09(1H,s),6.61(1H,s),6.65(1H,d,8.3 Hz),7.08(1H,s),7.25(1H,dd,8.3Hz,2.0Hz),7.26(1H, d,2.0Hz) | ||
176 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-aminomethyl-1,2,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 139-140 (EtOH) | 31 -482.2° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.0Hz),2.08(3H,s),2.59 (1H,dd,13.9Hz,13.9Hz),2.95(1H,dd,13.9Hz,5.1Hz), 3.87(2H,s),4.95(1H,m),5.50(2H,s),6.03(1H,s),6.07 (1H,s),6.57(1H,s),6.65(1H,d,8.1Hz),7.05(1H,s), 7.21(1H,d,br,8.1Hz),7.26(1H,s,br) | ||
177 | (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-{5-[1-(1E)-propylene-1-yl]-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 139-143 | 65 -498.9° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 1.21(3H,d,6.2Hz),1.86(1H,dd,6.8Hz, 1.8Hz),2.08(3H,s),2.59(1H,dd,14.0Hz,10.8Hz),2.98 (1H,dd,14.0Hz,5.4Hz),4.98(1H,m),5.53(2H,s,br), 6.03(1H,s),6.08(1H,s),6.32(1H,dq,15.7Hz,6.8Hz), 6.55(1H,dq,15.7Hz,1.8Hz),6.57(1H,s),6.44(1H,d, 8.4Hz),7.06(1H,s),7.22(1H,dd,8.4Hz,2.1Hz),7.26 (1H,d,2.1Hz) | ||
178 | (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-hexyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 180-181 | 75 -485.2° (c=0.5, CHCl 3) |
Method B | 1H NMR(DMSO-d 6)d 0.84(3H,t,7.0Hz),1.20(3H,d,6.1Hz), 1.2-1.3(6H,m),1.62(2H,m),2.07(3H,s),2.58(1H,dd, 13.9Hz,10.5Hz),2.82(2H,t,7.5Hz),2.95(1H,dd,13.9 Hz,5.4Hz),4.94(1H,m),5.49(2H,s),6.03(1H,s),6.08 (1H,s),6.57(1H,s),6.64(1H,d,8.4Hz),7.05(1H,s), 7.19(1H,dd,8.4Hz,2.2Hz),7.25(1H,d,2.2Hz) | ||
179 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl | 175-180 | 61 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
-(5,6-dihydro-5-oxo-4H-1,3,4-thiadiazine-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | -686.0° (c=0.5, CHCl 3) | ||
Method B | 1H NMR(DMSO-d 6)d 1.15(3H,d,6.4Hz),2.05(3H,s),2.48 (1H,dd,13.8Hz,10.4Hz),2.85(1H,dd,13.8Hz,5.3Hz), 3.32(2H,s),4.75(1H,m),5.42(2H,s),6.04(1H,s),6.07 (1H,s),6.55(1H,s),6.61(1H,d,8.4Hz),6.99(1H,s), 7.15(1H,dd,8.4Hz,1.8Hz),7.26(1H,d,1.8Hz),10.47 (1H,s) | ||
180 | (R)-5-(4-aminophenyl)-8-methyl-7-(1,3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 187-190 | 78 -604.0° (c=0.5, CHCl 3) |
Method A | 1H NMR(CDCl 3)d 1.45(3H,d,6.0Hz),2.73(1H,dd,14.0Hz, 10.5Hz),2.86(1H,dd,14.0Hz,5.5Hz),3.99(2H,s,br), 4.94(1H,m),5.98(1H,d,1.0Hz),6.02(1H,d,1.0Hz),6.64 (1H,s),6.68(2H,d,8.0Hz),6.82(1H,s),7.56(2H,d,8.0 Hz),7.99(1H,s) | ||
181 | (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 140-145 | 85 -554.8° (c=0.5, CHCl 3) |
Method B | MS:EI(70eV):[M] +.:391,m/z:266 CI:[M+H] +:392 | ||
182 | (R)-5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 98-100 | 92 -266.0° (c=0.5, CHCl 3) |
Method C | 1H NMR(DMSO-d 6)d 1.18(3H,d,6.0Hz),2.50(3H,s),2.65 (1H,dd,14.0Hz,9.9Hz),2.98(1H,dd,14.0Hz,4.9Hz), 4.95(1H,m),5.95(2H,s),6.05(1H,s),6.09(1H,s),6.63 (1H,s),6.83(1H,d,8.6Hz),7.07(1H,s),7.24(1H,dd, 8.6Hz,2.0Hz),7.44(1H,d,2.0Hz) MS:EI(70eV):[M] +.:427/429,m/z:412/414,313/315,286/288, 160 CI:[M+H] +:428/30,[M] +.:427/429 | ||
183 | (R)-5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | 105-109 | 91 -350.0° (c=0.5, CHCl 3) |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
Method C | 1H NMR(DMSO-d 6)d 1.20(3H,d,6.1Hz),2.67(1H,dd,14.1 Hz,10.3Hz),3.00(1H,dd,14.1Hz,5.4Hz),3.32(3H,s), 4.58(1H,d,13.0Hz),4.62(1H,d,13.0Hz),5.01(1H,m), 5.98(2H,s,br),6.05(1H,s),6.09(1H,s),6.64(1H,s), 6.84(1H,d,8.4Hz),7.07(1H,s),7.29(1H,dd,8.4Hz, 1.8Hz),7.44(1H,d,1.8Hz) MS:EI(70eV):[M] +.:457/459,m/z:442/444,313/315,286/288, 160 CI:[M+H] +:458/60,[M] +.:457/459 | ||
184 | (R)-5-(4-amino-2-bromo-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine | Foam | 98 |
Method A | 1H NMR(CDCl 3)d 1.25(3H,d,6.2Hz),2.25(3H,s),2.53(3H, s),2.93(1H,dd,14.6Hz,7.3Hz),3.25(1H,dd,14.6Hz, 3.1Hz),3.4-4.3(2H),5.43(1H,m),5.92(1H,d,1.4Hz), 5.93(1H,d,1.4Hz),6.36(1H,s),6.69(1H,d,8.1Hz),6.72 (1H,s),7.12(1H,d,8.1Hz) MS:EI(70eV):[M] +.:485/487,m/z:470/472,406,265,219 CI:[M+H] +:486/488 | ||
185 | (±)-5-(4-aminophenyl)-8-methyl-7-(3-methyl-isoxazole-5-bases)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 100-103 | 87 |
Method C | 1H NMR(DMSO-d 6)d 1.16(3H,d,6.5Hz),2.07(3H,s),2.45 (1H,dd,14.0Hz,11.5Hz),2.88(1H,dd,14.0Hz,6.0Hz), 4.58(1H,m),5.26(1H,s),5.70(2H,s),6.02(1H,s),6.07 (1H,s),6.56(1H,s),6.58(2H,d,8.5Hz),7.03(1H,s), 7.36(2H,d,8.5Hz) MS:EI(70eV):[M] +.:376,m/z:306,265,252,82,54 CI:[M+H] +:377,[M] +.:376 | ||
186 | (R)-5-(4-aminophenyl)-8-methyl-7-(1,2,3-thiadiazoles-5-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 220-221 | 33 -705.0° (c=0.5, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.18(3H,d,6.1Hz),2.60(1H,dd,13.8 Hz,11.4Hz),2.95(1H,dd,13.8Hz,5.1Hz),4.75(1H,m), 5.81(2H,s,br),6.03(1H,s),6.08(1H,s),6.59(1H,s), 6.61(2H,d,8.4Hz),7.08(1H,s),7.35(2H,d,8.4Hz), 8.10(1H,s) MS:EI(70eV):[M] +.:379,m/z:351,336,279,252 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
CI:[M+H] +:380,m/z:352 | |||
187 | (±)-5-(4-aminophenyl)-8-methyl-7-(2-methyl isophthalic acid, 3-oxazole-5-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 148-150 | 88 |
Method A | 1H NMR(DMSO-d 6)d 1.07(3H,d,5.3Hz),2.23(3H,br),2.40 (1H,dd,13.7Hz,7.7Hz),2.83(1H,dd,13.7Hz,5.6Hz), 4.31(1H,m),5.58(s,br),6.03(1H,s),6.05(1H,s),6.54 (2H,d,8.2Hz),6.57(1H,s),7.00(1H,s),7.28(2H,d,8.2 Hz) MS:EI(70eV):[M] +.:376,m/z:335,306,265,252 CI:[M+H] +:377 | ||
188 | (±)-5-(4-aminophenyl)-8-methyl-7-(2,4-dimethyl-1,3-oxazole-5-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 180-182 | 92 |
Method A | 1H NMR(DMSO-d 6)d 0.94(3H,d,6.1Hz),1.76(3H,s),2.29 (3H,s),2.43(1H,dd,13.8Hz,3.3Hz),2.79(1H,dd,13.8 Hz,6.6Hz),4.13(1H,m),5.53(s,br),6.07(1H,s),6.08 (1H,s),6.52(2H,d,8.4Hz),6.58(1H,s),6.99(1H,s), 7.18(2H,d,8.4Hz) MS:EI(70eV):[M] +.:390,m/z:349,334,306,279,265,252 CI:[M+H] +:391,[M] +.:390 | ||
189 | (R)-5-(4-amino-3, the 5-3,5-dimethylphenyl)-8-methyl-7-(thiazol-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 202-203 | 75 -686.0° (c=0.3, CHCl 3) |
Method A | MS:EI(70eV):[M] +.:406,m/z:391,307,280 | ||
190 | (R)-5-(4-amino-3, the 5-3,5-dimethylphenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | 280-281 | 74 -538.0° (c=0.5, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.18(3H,d,6.1Hz),2.11(6H,s),2.49 (3H,s),2.57(1H,dd,13.9Hz,10.8Hz),2.95(1H,dd,13.9 Hz,5.1Hz),4.93(1H,m),5.19(2H,s,br),6.03(1H,d,0.5 Hz),6.08(1H,d,0.5Hz),6.56(1H,s),7.05(1H,s),7.12 (2H,s) MS:EI(70ey):[M] +.:421,m/z:406,307,306,280 CI:[M+H] +:422 |
The embodiment numbering | Title | Fusing point (℃) recrystallization solvent | Productive rate (%) [α] D |
191 | (R)-5-(4-amino-3, the 5-3,5-dimethylphenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine also | 148-150 | 87 -705.0° (c=0.5, CHCl 3) |
Method A | MS:EI(70eV):[M] +.:405,m/z:280,245,134,83,77 CI:[M+H] +:406 | ||
192 | (R)-5-(4-aminophenyl)-8-methyl-7-(2-methyl-3-oxo-2,3-dihydro-1,2,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is benzodiazepine also-[4,5-h] [2,3] | 185-190 | 60 -45.0° (c=0.47, CHCl 3) |
Method A | 1H NMR(DMSO-d 6)d 1.19(3H,d,6.5Hz),2.69(1H,dd,14.0 Hz,10.0Hz),3.00(1H,dd,14.0Hz,4.5Hz),3.05(3H,s), 4.89(1H,m),5.81(2H,s,br),6.05(1H,s),6.08(1H,s), 6.58(2H,d,8.5Hz),6.59(1H,s),7.06(1H,s),7.26(2H, d,8.5Hz) MS:EI(70eV):[M] +.:409,m/z:279,252 CI:[M+H] +:410,[M] +.:409 | ||
193 | (±)-5-(4-aminophenyl)-8-methyl-7-(5,5-dimethyl-4-oxo-4,5-thiazoline-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine | 124-130 is unbodied | 75 |
Method A | MS:EI(70eV):[M] +.:422,m/z:407,279,252 CI:[M+H] +:423 |
Embodiment 194
(R)-and 7-(4,5-dihydro-thiazol-2-yl)-5-(4-chloro-phenyl-)-8-methyl-8, the 9-dihydro -7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 7-(tert-butoxycarbonyl)-5-(4-chloro-phenyl-)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
According to document (Anderson etc., J.Am.Chem.Soc.
117: 12358 (1995)) described synthetic method, just replace acethydrazide and 4-nitrobenzaldehyde respectively with tert-butyl carbazate and 4-chlorobenzaldehyde, prepared this compound.Isolate foamed title product, be used for next step.
Step B
(R)-and 5-(4-chloro-phenyl-)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
The product that 11.0g (28.2mmol) is obtained in steps A is dissolved into 120ml and contains in the ethyl acetate of 10% hydrochloric acid, and stirs 3 hours, uses yellow soda ash and water washing solution then.After drying and the evaporation, recrystallization crude product in ethyl acetate generates 5.07g (57%) title compound.Fusing point: 185-187 ℃; [α]
D:+241.0 ° of (c=0.5; CHCl
3).
Step C
(R)-and 5-(4-chloro-phenyl-)-8-methyl-7-thiocarbamyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also
The mixture that will contain product, 0.73g (7.5mmol) potassium sulfocyanate and 16ml acetate that 1.57g (5.0mmol) obtains in step B stirred 3 hours at 110 ℃.After the cooling, add entry, and leach sedimentary crystallization, wash with water and drying, generate 1.73g (92%) title compound.Fusing point: 208-212 ℃.
Step D
According to embodiment 9 described methods, (1.0g is 2.66mM) with 2.20g (10.7mmol) 2-bromoethyl amine hydrobromide reaction in the 5ml dimethyl formamide to make the compound that obtains in step C.By the column chromatography separated product, be added to recrystallization in the ethyl acetate, generate 0.26g (25%) title compound.Fusing point: 216-219 ℃; [α]
D:+326.7 ° of (c=0.5; CHCl
3).
1H NMR(DMSO-d
6)δ1.11(3H,d,5.7Hz),2.79(1H,dd,14.7Hz,6.4Hz),3.16(1H,dd,14.7Hz,1.7Hz),3.25(2H,m),4.16(2H,m),4.28(2H,m),5.25(1H,m),5.99(2H,s),6.59(1H,s),6.71(1H,s)7.34(2H,d,8.0Hz),7.53(2H,d,8.0Hz)
Embodiment 195
(R)-and 5-(4-chloro-phenyl-)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
According to embodiment 1 described method, (0.55g is 1.47mmol) with the reaction of 0.22ml (1.47mmol) bromoacetaldehyde diethyl acetal to make the compound that obtains in the step C of embodiment 194.The mixture that uses normal hexane-ethyl acetate (2: 1) is as eluent, by column chromatography purifying crude product.Concentrate contain the fraction of title compound after, use the water treatment resistates, generation 0.40g (68%) title compound.Fusing point: 116-117 ℃; [α]
D:+118.6 ° of (c=0.5; CHCl
3).
1H NMR(CDCl
3)δ1.22(3H,d,6.4Hz),2.83(1H,dd,14.6Hz,7.2Hz),3.18(1H,dd,14.6Hz,3.4Hz),5.38(1H,m),6.01(2H,s),6.61(1H,s),6.69(1H,d,3.7Hz),6.78(1H,s),7.32(1H,d,3.7Hz),7.38(2H,d,8.6Hz),7.58(2H,d,8.6Hz)
Embodiment 196
(R)-5-(4-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine
Steps A
(R)-and 5-(4-chloro-phenyl-)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine -7-carbon sulfenyl muriate also
According to about the described method of initial compounds XI, make the compound (2.20g, 7.0mmol) reaction that in the step B of embodiment 194, obtain.The mixture that uses normal hexane-ethyl acetate (4: 1) by column chromatography purifying crude product, generates the title compound of 1.38g (49%) solid foam shape as eluent.
Step B
According to the described method of embodiment 28 method B, the product that uses 1.0g (2.48mmol) to obtain in steps A prepares title compound.By the column chromatography separated product, use water cure, generate 0.42g (52%).Fusing point: 105-108 ℃; [α]
D:+103.2 ° of (c=0.5; CHCl
3).
1H NMR(CDCl
3)δ1.25(3H,d,6.2Hz),2.61(3H,s),2.84(1H,dd,14.3Hz,7.1Hz),3.18(1H,dd,14.3Hz,3.6Hz),5.35(1H,m),6.02(2H,s),6.57(1H,s),6.79(1H,s),7.38(2H,d,8.2Hz),7.52(2H,d,8.2Hz)
Embodiment 197
(R)-5-(4-acetylamino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4- Thiadiazoles-2-yl)-and 8.9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzene And diaza
According to the described general method of embodiment 120-131, the compound of acetylize embodiment 119.Fusing point: 267-269 ℃.Productive rate: 67%; [α]
D:-121.0 ° of (c=0.5; CHCl
3).
1H NMR(DMSO-d
6)δ1.16(3H,d,6.1Hz),2.10(3H,s),2.25(3H,s),2.50(3H,s),2.79(1H,dd,14.0Hz,8.2Hz),3.09(1H,dd,14.0Hz,4.0Hz),5.08(1H,m),6.07(1H,s),6.09(1H,s),6.55(1H,s),7.07(1H,s),7.31(1H,d,8.3Hz),7.38(1H,8,br),7.59(1H,d,br,8.3Hz),9.36(1H,s)
Embodiment 198
(R)-1-methyl-3{2-methyl-4-[8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2- Base)-8,9-dihydro-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -5-yl] }-phenylurea
Make the material that in embodiment 119, obtains (1.03g, 2.53mmol) with the 20ml methylene dichloride in 0.75ml (12.6mmol) methyl isocyanate room temperature reaction 6 days.Evaporating solvent generates crude product, and the mixture that uses hexane-ethyl acetate (2: 1) carries out purifying as eluent by column chromatography, generates 0.67g (57%) title compound.Fusing point: 237-242 ℃; [α]
D:-140.0 ° of (c=0.5; CHCl
3).
1H NMR(DMSO-d
6)δ1.17(3H,d,6.4Hz),2.21(3H,s),2.51(3H,s),2.66(3H,d,4.6Hz),2.71(1H,dd,14.2Hz,9.4Hz),3.04(1H,dd,14.2Hz,4.5Hz),5.02(1H,m),6.05(1H,d,0.9Hz),6.08(1H,d,0.9Hz),6.55(1H,s),6.56(1H,q,4.6Hz),7.07(1H,s),7.30(1H,dd,8.4Hz,2.0Hz),7.34(1H,d,2.0Hz),7.82(1H,s),8.00(1H,d,8.4Hz)
Embodiment 199
(R)-and 2-methyl-4-[8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-two Hydrogen-7H-1,3-Dioxole also
[4,5-h] [2,3] benzodiazepine -5-yl]-benzene The aminocarbamic acid ethyl ester
Under the situation that has 0.40ml (2.88mmol) triethylamine, make the material that in embodiment 119, obtains (0.90g, 2.21mmol) with Vinyl chloroformate (0.30ml, 3.15mmol) in methylene dichloride room temperature reaction 6 hours.With dilute hydrochloric acid and sodium hydrogen carbonate solution washing soln, drying, and be evaporated to dried.The mixture that uses hexane-ethyl acetate (2: 1) by column chromatography purifying resistates, generates 0.45g (42%) title product as eluent.Fusing point: 241-244 ℃; [α]
D:-180.0 ° of (c=0.5; CHCl
3).
1H NMR(DMSO-d
6)δ1.15(3H,d,6.1Hz),1.25(3H,t,7.0Hz),2.25(3H,s),2.51(3H,s),2.78(1H,dd,14.3Hz,8.7Hz),3.05(1H,dd,14.3Hz,4.3Hz),4.13(2H,q,7.0Hz),5.07(1H,m),6.06(1H,d,0.7Hz),6.08(1H,d,0.7Hz),6.55(1H,s),7.07(1H,s),7.31(1H,dd,8.3Hz,2.0Hz),7.36(1H,d,2.0Hz),7.53(1H,d,8.3Hz),8.96(1H,s)
Other collection of compound of the present invention in following table, example the AMPA antagonistic activity of formula (I) compound.(the application front record with quoted from corresponding in vitro and body in research method and relevant document.)
Table 13. (continuous table 1)
Inhibition to " spreading depression " in the chicken retina
Compound (embodiment numbering)/IC 50μM | |||||
119 | 165 | 166 | 167 | 168 | 182 |
0.069 | 0.113 | 0.201 | 0.064 | 0.082 | 0.020 |
Table 14. (continuous table 2)
Pressing down of the ion(ic)current that 5 μ M AMPA are caused that records by full cell patch clamping method
System
Compound (embodiment numbering)/IC 50μM | |||||
119 | 165 | 166 | 167 | 168 | 182 |
0.026 | 0.024 | 0.028 | 0.070 | 0.011 | 0.031 |
Table 15. (continuous table 3)
Anti-convulsant activity in the research mouse
Method | Compound (embodiment numbering)/ED 50mg/kg po. | |||||
119 | 165 | 166 | 167 | 168 | 182 | |
MES 60’ | 2.87 | 3.99 | 4.01 | 5.85 | 4.49 | 6.17 |
MES 30’ | 2.15 | 2.39 | 4.54 | 4.78 | 2.21 | 5.08 |
Pentetrazole | 5.00 | 10.10 | 9.18 | 9.66 | 6.90 | 8.37 |
Strychnine | 8.40 | 10.20 | 7.29 | 10.50 | 10.00 | 5.90 |
Bemegride | 5.70 | 10.00 | 7.77 | 8.33 | 6.70 | 7.94 |
Eximine | 2.50 | 5.79 | 13.30 | 12.70 | 10.60 | 8.44 |
Nicotine | 6.30 | 18.60 | 21.80 | 10.80 | 17.70 | 24.20 |
4-AP | 2.68 | 8.60 | 6.81 | 10.80 | 4.60 | 5.44 |
3-MPA | 3.37 | 8.53 | 9.92 | 10.30 | 4.62 | 7.57 |
Abbreviation: MES=maximal electroshock outbreak; The 4-AP=4-aminopyridine; 3-MPA=3-sulfydryl-propionic acid
Table 16. (continuous table 4)
Muscle relaxant activities in mouse
Compound (embodiment numbering) | Sieve ED inclines 50Intraperitoneal (mg/kg) | Rotarod ED 50Intraperitoneal (mg/kg) |
119 | 2.49 | 0.51 |
165 | 2.94 | 0.91 |
166 | 3.27 | 0.86 |
167 | 4.24 | 0.80 |
168 | 3.58 | 0.80 |
182 | 5.84 | 2.61 |
Table 17. (continuous table 5)
In rat to ischemic inhibition
Compound (embodiment numbering) | Dosage mg/kg intravenously (6x, per 30 minutes) | The infarct size of comparing with control group reduces % | |||
30 minutes | 120 minutes | 180 minutes | 240 minutes | ||
The time of blocking the back first treated | |||||
119 | 0.5 | 7 | |||
1.0 | 38 | ||||
1.5 | 51* | 21 | |||
2.0 | 56* | 44** | 21 |
* p<0.05; * p<0.01; Carrying out the Dunnett check according to ANOVA calculates
(Dunnett J.Amer.Statist.Ass.
50:1096(1955))
Noted earlier as this specification sheets, difference is the animal (Lewis rat, female) of using 10 heavy 140-160g in every group, in rat autoimmunity encephalomyelitis model, has further studied compound of the present invention.The result is shown in table 19 and 20.
Table 18. (continuous table 6)
Have 2 of AMPA antagonistic activity, 3-benzodiazepine in the Lewis rat from
The effect of the clinical symptom of body immunity encephalomyelitis
Compound (embodiment numbering) | Dosage | Neurological symptoms result (variation compared with the control, %) female rats | ||
The mg/kg intraperitoneal | mg/kg p.o. | 0-8 days | 0-14 days | |
119 | 3.75 1.875 1.0 0.5 0.2 | 3.75 1.875 1.0 0.5 | -97*** -72* -75** -33 -36 -64*** -50** -20 +2 | -90** -71** -72** -35 -37 -61*** -50** -23 -1 |
166 | 7.5 3.75 | -51* -6 | -53* -9 | |
168 | 7.5 3.75 | -55* -16 | -56* -23 |
About statistics, referring to table 20.
Table 19. (continuous table 7)
Has 2 of AMPA antagonist feature, 3-benzodiazepine derivative back 24 days to immunity
The influence of the histology of autoimmunity encephalomyelitis and clinical symptom in the Lewis rat
Compound (embodiment numbering) | Dosage | Histopathology symptom (changing %) | Neurological symptoms result (changing %) | |
The mg/kg intraperitoneal | mg/kg p.o. | Female rats | ||
119 | 3.75 1.875 1.0 0.5 0.2 | 3.75 1.875 1.0 0.5 | +3 -8 -3 -13 +2 -32 -42 -21 -16 | -90** -71** -72** -35 -37 -61*** -50** -23 -1 |
* p<0.05; * p<0.01; * * p<0.001 (Mann-Whitney check).
Table 20. (continuous table 8)
Have 2 of AMPA antagonist feature, 3-benzodiazepine derivative is to different chemistry
The effect of trembling of agent inductive CD1 mouse
Compound (embodiment numbering) | ED 50(mg/kg po.) | |
Oxotremorine 1mg/kg intraperitoneal | GYKI 20039 10mg/kg intraperitoneal | |
119 | 1.38(0.80-2.38) | 2.21(1.37-3.56) |
165 | 4.63(3.66-5.85) | 5.34(3.90-7.31) |
166 | 2.74(1.97-3.00) | 4.54(3.69-5.58) |
167 | 4.81(3.45-6.72) | 7.73(4.99-11.98) |
168 | 3.29(2.63-4.12) | 4.11(3.22-5.45) |
182 | 2.66(1.24-5.72) | 3.64(2.37-5.57) |
Table 21. (continuous table 9)
Embodiment 119 described compounds to the Protalbinic acid sensitization and undertaken by suction
The bronchial hyperreactivity of the air flue of the BN-rat that antigen is attacked and the work of eosinophilia
With (mean+/-standard error, N=10 determine p by Student ' s t-check).
Compound (embodiment numbering) | |||
Parameter | Contrast | Attack | 119 3.0mg/kg po |
ED 50* | 5.19±0.07 | 5.97±0.29 | 4.35±0.36 |
p | 0.001 | 0.001 | |
MAX** | 100±0 | 154±21 | 82±7 |
p | 0.001 | 0.009 | |
Eosinocyte * * * | 0.15±0.03 | 1.17±0.18 | 1.16±0.24 |
p | 0.001 | NS |
* can cause 50% vagusstoff (Ach) concentration (log M) of shrinking compared with the control
* is in the relative contraction compared with the control of maximum Ach concentration
* * BALF eosinocyte number (* 10
6/ ml)
Not remarkable (p>0.05)
Equivalent
Although describe claimed invention in detail with reference to particular, those of ordinary skill in the art can understand, can carry out multiple changes and improvements to claimed invention, and not depart from its spirit and scope.Thereby, for example, only using normal experiment, those of ordinary skill in the art just will recognize the numerous equivalents that maybe can be sure of predetermined substance as herein described and method.Think these equivalents also within the scope of the invention, and contained by following claims.
Claims (24)
1. the compound of formula (I), wherein
R
3Represent at least 2 the heteroatomic heterocycles that contain of aromatics, saturated or fractional saturation that replace or unsubstituted 5-or 6-unit, wherein heteroatoms can be oxygen, sulphur or nitrogen-atoms, and when heterocycle contained 2 heteroatomss, one of them was not a nitrogen;
R
4, R
5, R
6And R
7Represent hydrogen atom, halogen atom, C independently of each other
1-C
3Alkyl, nitro, amino, wherein amino can be independently of each other by 1 or 2 following radicals replacement: C
1-C
3Alkyl, C
2-C
5Acyl group or C
2-C
5Carbalkoxy, or aminocarboxyl or C
2-C
5Alkyl amino-carbonyl; And
R
9Represent C
1-C
3The alkoxy or halogen atom,
R
10Represent hydrogen or halogen atom or
R
9And R
10Form C together
1-C
3Alkylene dioxo base; With
The steric isomer of described compound and acid salt.
2. according to the compound of claim 1, R wherein
3Heterocycle can be further replaced by one or more following substituting groups: C
1-C
5Alkyl, C
2-C
3Alkenyl, C
3-C
7Cycloalkyl, trifluoromethyl, C
1-C
3Alkoxyl group or phenyl, oxo, formyl radical, carboxyl or C
2-C
4Carbalkoxy, C
1-C
3Alkoxy methyl, halogen atom, hydroxymethyl, wherein hydroxyl can be alkylation or acidylate, C
1-C
3The alkylthio methyl, cyano methyl or amino methyl, wherein amino can be alkylation or acidylate.
3. according to the compound of claim 1, R wherein
3Be to be selected from: replacement and unsubstituted isoxazole, isothiazole, thiazole, thiazoline, 4-thiazolinone , oxazole , oxazoline, 1,2,3-thiadiazoles, 1,3,4-thiadiazoles, 1,3,4-Thiadiazoline-2-ketone, 1,2,4-Thiadiazoline-3-ketone, 1,4,2-Evil thiazoline, 1,3,4-oxadiazole, 1,2,3-triazoles, 1,3,4-triazole, 1,2,3, the 4-thiatriazole, tetrazolium, 1,3-thiazine-4-ketone and 1,3,4-thiadiazine-4-ketone ring.
4. according to the compound of claim 1, R wherein
3Be that replace or unsubstituted 1,3,4-thiadiazoles-2-base, 4,5-dihydro-thiazol-2-yl, 2-thiazolyl or 1,3,4-oxadiazole base group, R
5Be hydrogen atom or methyl, R
6Substituting group is an amino group, and R
9And R
10Represent methylene-dioxy together, or R
9Be chlorine atom or methoxy group, and R
10Be hydrogen or chlorine atom.
5. according to the compound of claim 1, it is selected from: (R)-5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(2-thiazolyl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(4,5-dihydro-thiazol-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-aminophenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-oxadiazole-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-8-methyl-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-propyl group-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-{5-[1-(1E)-propylene-1-yl]-1,3,4-thiadiazoles-2-yl }-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine also; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be benzodiazepine also-[4,5-h] [2,3]; (R)-and 5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methoxyl group-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole be [4,5-h] [2,3] benzodiazepine and its acid salt also.
6. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole are also-[4,5-h] [2,3] benzodiazepine or its additive salt.
7. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-7-(5-ethyl-1,3,4-thiadiazoles-2-yl)-and 8-methyl-8,9-dihydro-7H-1,3-dioxole are also-[4,5-h] [2,3] benzodiazepine or its acid salt.
8. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-propyl group-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole also [4,5-h] [2,3] benzodiazepine or its acid salt.
9. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole are also-[4,5-h] [2,3] benzodiazepine or its acid salt.
10. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole also-[4,5-h] [2,3] benzodiazepine or its acid salt.
11. compound according to claim 1, wherein said compound is (R)-5-(4-amino-3-aminomethyl phenyl)-8-methyl-7-{5-[1-(1E)-propylene-1-yl]-1,3,4-thiadiazoles-2-yl }-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine or its acid salt also.
12. according to the compound of claim 1, wherein said compound is (R)-5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methyl isophthalic acid, 3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1,3-dioxole are also-[4,5-h] [2,3] benzodiazepine or its acid salt.
13. compound according to claim 1, wherein said compound is (R)-5-(4-amino-3-chloro-phenyl-)-8-methyl-7-(5-methoxymethyl-1,3,4-thiadiazoles-2-yl)-8,9-dihydro-7H-1, the 3-dioxole is [4,5-h] [2,3] benzodiazepine or its acid salt also.
14. pharmaceutical composition, it contains each formula (I) compound or its steric isomer or its pharmacy acceptable salt among the with good grounds claim 1-14.
15. treatment and the handicapped method of glutaminate acute or that chronic neurodegenerative disease is relevant, it comprises the compound to the claim 1 of the object administering therapeutic significant quantity of this treatment of needs.
16. the method for claim 8, wherein said neurodegenerative disease is to be selected from: cerebral ischemia (apoplexy), brain and Spinal injury, Alzheimer, huntington's chorea, amyotrophic lateral sclerosis, AIDS-inductive dementia, essential tremor, Parkinson's disease, multiple sclerosis and the urinary incontinence.
17. the method for treatment epilepsy, it comprises the compound to the claim 1 of the effective anti-epileptic amount of object administering therapeutic of this treatment of needs.
18. alleviate the method for muscle spasm, it comprises the compound to the claim 1 of the effective relaxed muscle amount of object administering therapeutic of this treatment of needs.
19. treat acute and method chronic inflammatory disease, it comprises the compound to the claim 1 of the administration treatment effective antiinflammatory amount of this treatment of needs.
20. the method for claim 19, wherein Zhi Liao inflammatory diseases is the allergic inflammatory diseases of air flue.
21. the method for claim 20, the allergic inflammatory diseases of wherein said air flue is to be selected from: allergic rhinitis, endogenous or extrinsic bronchial asthma, acute or chronic bronchitis, chronic obstructive pulmonary disease and pulmonary fibrosis.
22. alleviate the method for pathological pain, it comprises the compound of using the claim 1 of the treatment significant quantity that eases the pain to the object of this treatment of needs.
23. treat the handicapped method of glutaminate in the acute or chronic disease of relevant with glutaminate dysfunction eye, it comprises the compound to the claim 1 of the object administering therapeutic significant quantity of this treatment of needs.
24. the method for claim 23, wherein Zhi Liao disease is selected from glaucoma or diabetic retinopathy.
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US10/358,053 US6858605B2 (en) | 2003-02-04 | 2003-02-04 | Substituted 2,3-benzodiazepine derivatives |
US10/358,053 | 2003-02-04 |
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Family
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CN (1) | CN1747938A (en) |
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TW (1) | TW200500347A (en) |
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CN104755473A (en) * | 2012-08-16 | 2015-07-01 | 拜耳医药股份有限公司 | 2,3-benzodiazepines |
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CA2517957C (en) | 2003-03-05 | 2012-01-24 | Toray Industries, Inc. | Aromatic polymer, film, electrolyte membrane and separator |
AU2004282018B2 (en) * | 2003-10-15 | 2009-07-23 | Sumitomo Chemical Company, Limited | 1,2,4-thiadiazole compounds and pests controlling composition containing the same |
WO2007077469A1 (en) * | 2005-12-30 | 2007-07-12 | Egis Gyógyszergyár | Optical isomers of dihydro-2,3-benzodiazepines and their stereoselective synthesis |
TW200902024A (en) * | 2007-04-02 | 2009-01-16 | Teva Pharma | Novel 2,3-benzodiazepine derivatives and their use as antipsychotic agents |
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HU191698B (en) * | 1984-07-27 | 1987-03-30 | Gyogyszerkutato Intezet | Process for producing new 1-aryl-5h-2beta-benzodiazepines |
HU219778B (en) * | 1990-12-21 | 2001-07-30 | Gyógyszerkutató Intézet Közös Vállalat | Process for producing n-acyl-2,3-benzodiazepine derivatives, their acid additional salts and pharmaceutical compositions containing them and a grop of the compounds and pharmaceutical compositions containing them |
HU206719B (en) | 1990-12-21 | 1992-12-28 | Gyogyszerkutato Intezet | Process for producing 1-/4-acylamino-phenyl/-7,8-methylenedioxy-5h-2,3-benzodiazepine derivatives, acid addicional salts and pharmaceutical compositions containing them |
HU219777B (en) | 1993-07-02 | 2001-07-30 | Gyógyszerkutató Intézet Kft. | Optical active 1-(4-nitrophenyl)-4-methyl-7,8-methylen dioxi-3,4-dihydro-5h-2,3-benzodiazepine and process for producing it |
DE4428835A1 (en) * | 1994-08-01 | 1996-02-08 | Schering Ag | New 3-substituted 3H-2,3-benzodiazepine derivatives, their production and use as medicines |
NZ292417A (en) * | 1994-08-31 | 1998-09-24 | Lilly Co Eli | 7h-1,3-dioxolo[4,5-h] [2,3]-benzodiazepine derivatives and medicaments |
TR199501071A2 (en) | 1994-08-31 | 1996-06-21 | Lilly Co Eli | Stereoselective process for producing dihydro-2,3-benzodiazepine derivatives. |
DE19604920A1 (en) * | 1996-02-01 | 1997-08-07 | Schering Ag | New 2,3-benzodiazepine derivatives, their production and use as medicines |
HU9600871D0 (en) | 1996-04-04 | 1996-05-28 | Gyogyszerkutato Intezet | New 2,3-benzodiazepine derivatives |
UA67749C2 (en) | 1997-08-12 | 2004-07-15 | Егіш Дьйодьсердьяр Рт. | 8-substituted-9h-1,3-dioxolo-[4,5-h][2,3]benzodiazepine being inhibitors of the ampa/kainite receptor |
PL338681A1 (en) | 1997-08-12 | 2000-11-20 | Egyt Gyogyszervegyeszeti Gyar | Derivatives of 1,3-dioxolo/4,5-h/2,3-benzodiazepins as inhibitors of ampa/cainate receptors |
HU227128B1 (en) | 1999-07-07 | 2010-07-28 | Egyt Gyogyszervegyeszeti Gyar | New 2,3-benzodiazepine derivatives |
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Cited By (2)
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CN104755473A (en) * | 2012-08-16 | 2015-07-01 | 拜耳医药股份有限公司 | 2,3-benzodiazepines |
CN104755473B (en) * | 2012-08-16 | 2017-03-08 | 拜耳医药股份有限公司 | 2,3 benzodiazepine * |
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US6858605B2 (en) | 2005-02-22 |
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NO20054067D0 (en) | 2005-09-01 |
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ZA200505352B (en) | 2007-01-31 |
EP1592673A4 (en) | 2006-10-25 |
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US20070027143A1 (en) | 2007-02-01 |
NO20054067L (en) | 2005-10-25 |
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